Agbaba, Danica

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orcid::0000-0001-5907-9823
  • Agbaba, Danica (258)
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Author's Bibliography

Prevojna HILIC/RP tačka - biomimetički retencioni parametar

Obradović, Darija; Agbaba, Danica; Lazović, Saša

(Savez farmaceutskih udruženja Srbije, 2023)

TY  - CONF
AU  - Obradović, Darija
AU  - Agbaba, Danica
AU  - Lazović, Saša
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5356
AB  - U uslovima su kojima su istovremeno prisutni dualni hidrofilni (HILIC) i reverzno-fazni (RP)
mehanizmi ispitan je retencioni profil liganada imidazolinskih i serotoninskih receptora (1).
Razmotreno je biomimetičko značenje parametra retencije (prevojna tačka), koji definišu uslove u
kojima dolazi do smene videćih mehanizama interakcije. Retencioni profil 43 liganada
imidazolinskih i serotoninskih receptora je ispitan na Acclaim Mixed-Mode HILIC-1 koloni. Kao
mobilna faza korišćena je smeša acetonitrila i 20 mM amonijum-acetata (pH 6). Hromatografsko
ponašanje definisano je kao zavisnost retencionog parametra logk u odnosu na udeo acetonitrila u
mobilnoj fazi (φ) korišćenjem multimodalne jednačine (2). Prevojna tačka HILIC/RP regiona
izračunata je kao minimalna vrednost dobijene funkcije. Uočeno je da dobijene vrednosti prevojne
tačke korelišu sa lipofilnom profilnom ispitivanih jedinjenja (r > 0.70), potencijalom vezivanja za
ukupne proteine plazme (r > 0.77), kao i procentom apsorpcije leka iz gastrointesinalnog trakta (r >
0.56). Fizičko-hemijske interakcije koje utiču na vezivanje ispitivanih jedinjenja za
arilhidrokarbonske receptore (NR.AhR) u organizmu, uključene u regulaciju toksikološkog
potencijala, takođe utiču i na vrednosti prevojne prevojne tačke (r > 0.60). Na osnovu dobijenih
rezultata, zaključuje se da se prevojna tačka dualnih HILIC/RP interakcija može uspešno primeniti u
preliminarnoj karakterizaciji biofarmaceutskog i farmakokinetičkog profila liganada imidazolinskih
i serotoninskih receptora.
AB  - The retention profile of imidazoline and serotonin receptor ligands was investigated in dual
hydrophilic (HILIC) and reversed-phase (RP) interaction mode (1). The biomimetic meaning of the
turining point that defines the switch between the leading retention mechanisms was discussed. The
retention profile of 43 imidazoline and serotonin receptor ligands was investigated on an Acclaim
Mixed-Mode HILIC-1 column. A mixture of acetonitrile and 20 mM ammonium acetate (pH 6) was
used as the mobile phase. The retention was defined as the change of the parameter logk in relation
to the volume fraction of acetonitrile in the mobile phase (φ) using the multimodal equation (2). The
turning point of the HILIC/RP region was calculated as the minimum value of the multimodal
equation. The obtained values of the turning point correlate with the lipophilic profile of the tested
compounds (r > 0.70), as well as with the binding potential for total plasma proteins (r > 0.77), and
the percentage of drug absorption from the gastrointestinal tract (r > 0.56). The physico-chemical
interactions that affect the binding of the tested compounds to arylhydrocarbon receptors (NR.AhR)
in the organism, involved in the regulation of toxicological potential, also affect the turning point
values (r > 0.60). It can be concluded that the turning point of dual HILIC/RP interactions can be
successfully applied in the preliminary characterization of the biopharmaceutical and
pharmacokinetic profile of imidazoline and serotonin receptor ligands.
PB  - Savez farmaceutskih udruženja Srbije
C3  - Arhiv za farmaciju
T1  - Prevojna HILIC/RP tačka - biomimetički retencioni parametar
T1  - Turning HILIC/RP point - biomimetic retention parameter
VL  - 73
IS  - Supp. 4
SP  - S95
EP  - S96
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5356
ER  - 
@conference{
author = "Obradović, Darija and Agbaba, Danica and Lazović, Saša",
year = "2023",
abstract = "U uslovima su kojima su istovremeno prisutni dualni hidrofilni (HILIC) i reverzno-fazni (RP)
mehanizmi ispitan je retencioni profil liganada imidazolinskih i serotoninskih receptora (1).
Razmotreno je biomimetičko značenje parametra retencije (prevojna tačka), koji definišu uslove u
kojima dolazi do smene videćih mehanizama interakcije. Retencioni profil 43 liganada
imidazolinskih i serotoninskih receptora je ispitan na Acclaim Mixed-Mode HILIC-1 koloni. Kao
mobilna faza korišćena je smeša acetonitrila i 20 mM amonijum-acetata (pH 6). Hromatografsko
ponašanje definisano je kao zavisnost retencionog parametra logk u odnosu na udeo acetonitrila u
mobilnoj fazi (φ) korišćenjem multimodalne jednačine (2). Prevojna tačka HILIC/RP regiona
izračunata je kao minimalna vrednost dobijene funkcije. Uočeno je da dobijene vrednosti prevojne
tačke korelišu sa lipofilnom profilnom ispitivanih jedinjenja (r > 0.70), potencijalom vezivanja za
ukupne proteine plazme (r > 0.77), kao i procentom apsorpcije leka iz gastrointesinalnog trakta (r >
0.56). Fizičko-hemijske interakcije koje utiču na vezivanje ispitivanih jedinjenja za
arilhidrokarbonske receptore (NR.AhR) u organizmu, uključene u regulaciju toksikološkog
potencijala, takođe utiču i na vrednosti prevojne prevojne tačke (r > 0.60). Na osnovu dobijenih
rezultata, zaključuje se da se prevojna tačka dualnih HILIC/RP interakcija može uspešno primeniti u
preliminarnoj karakterizaciji biofarmaceutskog i farmakokinetičkog profila liganada imidazolinskih
i serotoninskih receptora., The retention profile of imidazoline and serotonin receptor ligands was investigated in dual
hydrophilic (HILIC) and reversed-phase (RP) interaction mode (1). The biomimetic meaning of the
turining point that defines the switch between the leading retention mechanisms was discussed. The
retention profile of 43 imidazoline and serotonin receptor ligands was investigated on an Acclaim
Mixed-Mode HILIC-1 column. A mixture of acetonitrile and 20 mM ammonium acetate (pH 6) was
used as the mobile phase. The retention was defined as the change of the parameter logk in relation
to the volume fraction of acetonitrile in the mobile phase (φ) using the multimodal equation (2). The
turning point of the HILIC/RP region was calculated as the minimum value of the multimodal
equation. The obtained values of the turning point correlate with the lipophilic profile of the tested
compounds (r > 0.70), as well as with the binding potential for total plasma proteins (r > 0.77), and
the percentage of drug absorption from the gastrointestinal tract (r > 0.56). The physico-chemical
interactions that affect the binding of the tested compounds to arylhydrocarbon receptors (NR.AhR)
in the organism, involved in the regulation of toxicological potential, also affect the turning point
values (r > 0.60). It can be concluded that the turning point of dual HILIC/RP interactions can be
successfully applied in the preliminary characterization of the biopharmaceutical and
pharmacokinetic profile of imidazoline and serotonin receptor ligands.",
publisher = "Savez farmaceutskih udruženja Srbije",
journal = "Arhiv za farmaciju",
title = "Prevojna HILIC/RP tačka - biomimetički retencioni parametar, Turning HILIC/RP point - biomimetic retention parameter",
volume = "73",
number = "Supp. 4",
pages = "S95-S96",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5356"
}
Obradović, D., Agbaba, D.,& Lazović, S.. (2023). Prevojna HILIC/RP tačka - biomimetički retencioni parametar. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije., 73(Supp. 4), S95-S96.
https://hdl.handle.net/21.15107/rcub_farfar_5356
Obradović D, Agbaba D, Lazović S. Prevojna HILIC/RP tačka - biomimetički retencioni parametar. in Arhiv za farmaciju. 2023;73(Supp. 4):S95-S96.
https://hdl.handle.net/21.15107/rcub_farfar_5356 .
Obradović, Darija, Agbaba, Danica, Lazović, Saša, "Prevojna HILIC/RP tačka - biomimetički retencioni parametar" in Arhiv za farmaciju, 73, no. Supp. 4 (2023):S95-S96,
https://hdl.handle.net/21.15107/rcub_farfar_5356 .

Design of experiments and Derringer's desirability function in optimisation and validation of RP-HPLC method for the analysis of enrofloxacin and its impurities

Dokmanović, Jelena; Kasagić-Vujanović, Irena; Gagić, Žarko; Nikolić, Katarina; Čarapić, Marija; Agbaba, Danica

(Akademiai Kiado ZRt., 2023)

TY  - JOUR
AU  - Dokmanović, Jelena
AU  - Kasagić-Vujanović, Irena
AU  - Gagić, Žarko
AU  - Nikolić, Katarina
AU  - Čarapić, Marija
AU  - Agbaba, Danica
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4474
AB  - Using the Design of Experiments methodology (Response-Surface Methodology and Derringer's Desirability Function), a simple, fast and robust RP-HPLC method was developed for the analysis of enrofloxacin (EFC), its impurity A (fluoroquinolonic acid, FQ) and impurity B (ciprofloxacin, CPX). Gradient elution of samples was performed on a Zorbax Eclipse XDB C18 column (150 × 4.6 mm, 3.5 μm) with a mobile phase consisting of 32 mM phosphate buffer pH 3.5-methanol (0 min-19.6% methanol; 15.5 min-19.6% methanol; 29.5 min-80% methanol; 30 min-19.6% methanol; 35 min-19.6% methanol), delivered at a flow rate of 1.5 mL min-1, wavelength of detection 278 nm (for EFX and CFX) and 265 nm for FQ. A good linear response was achieved in the range 15-35 μg mL-1 (EFX) and LOQ-150% for impurities (CFX and FQ). Other validation parameters were also tested: precision, accuracy, sensitivity and robustness. The developed method was shown to be simple, practical and suitable for the analysis of EFC and its impurities (CPX, FQ) in veterinary drugs.
PB  - Akademiai Kiado ZRt.
T2  - Acta Chromatographica
T1  - Design of experiments and Derringer's desirability function in optimisation and validation of RP-HPLC method for the analysis of enrofloxacin and its impurities
DO  - 10.1556/1326.2022.01111
ER  - 
@article{
author = "Dokmanović, Jelena and Kasagić-Vujanović, Irena and Gagić, Žarko and Nikolić, Katarina and Čarapić, Marija and Agbaba, Danica",
year = "2023",
abstract = "Using the Design of Experiments methodology (Response-Surface Methodology and Derringer's Desirability Function), a simple, fast and robust RP-HPLC method was developed for the analysis of enrofloxacin (EFC), its impurity A (fluoroquinolonic acid, FQ) and impurity B (ciprofloxacin, CPX). Gradient elution of samples was performed on a Zorbax Eclipse XDB C18 column (150 × 4.6 mm, 3.5 μm) with a mobile phase consisting of 32 mM phosphate buffer pH 3.5-methanol (0 min-19.6% methanol; 15.5 min-19.6% methanol; 29.5 min-80% methanol; 30 min-19.6% methanol; 35 min-19.6% methanol), delivered at a flow rate of 1.5 mL min-1, wavelength of detection 278 nm (for EFX and CFX) and 265 nm for FQ. A good linear response was achieved in the range 15-35 μg mL-1 (EFX) and LOQ-150% for impurities (CFX and FQ). Other validation parameters were also tested: precision, accuracy, sensitivity and robustness. The developed method was shown to be simple, practical and suitable for the analysis of EFC and its impurities (CPX, FQ) in veterinary drugs.",
publisher = "Akademiai Kiado ZRt.",
journal = "Acta Chromatographica",
title = "Design of experiments and Derringer's desirability function in optimisation and validation of RP-HPLC method for the analysis of enrofloxacin and its impurities",
doi = "10.1556/1326.2022.01111"
}
Dokmanović, J., Kasagić-Vujanović, I., Gagić, Ž., Nikolić, K., Čarapić, M.,& Agbaba, D.. (2023). Design of experiments and Derringer's desirability function in optimisation and validation of RP-HPLC method for the analysis of enrofloxacin and its impurities. in Acta Chromatographica
Akademiai Kiado ZRt...
https://doi.org/10.1556/1326.2022.01111
Dokmanović J, Kasagić-Vujanović I, Gagić Ž, Nikolić K, Čarapić M, Agbaba D. Design of experiments and Derringer's desirability function in optimisation and validation of RP-HPLC method for the analysis of enrofloxacin and its impurities. in Acta Chromatographica. 2023;.
doi:10.1556/1326.2022.01111 .
Dokmanović, Jelena, Kasagić-Vujanović, Irena, Gagić, Žarko, Nikolić, Katarina, Čarapić, Marija, Agbaba, Danica, "Design of experiments and Derringer's desirability function in optimisation and validation of RP-HPLC method for the analysis of enrofloxacin and its impurities" in Acta Chromatographica (2023),
https://doi.org/10.1556/1326.2022.01111 . .

Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach

Tomić, Jovana; Đajić, Nevena; Agbaba, Danica; Otašević, Biljana; Malenović, Anđelija; Protić, Ana

(Akademiai Kiado ZRt., 2022)

TY  - JOUR
AU  - Tomić, Jovana
AU  - Đajić, Nevena
AU  - Agbaba, Danica
AU  - Otašević, Biljana
AU  - Malenović, Anđelija
AU  - Protić, Ana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4331
AB  - This paper is aimed at developing a gradient elution reversed-phase high-performance liquid chromatography (RP-HPLC) method for the separation of a complex mixture composed of ivabradine and its eleven impurities, in a reasonable timeframe. In order to obtain a robust and reliable HPLC method for separation of this mixture, Analytical Quality by Design (AQbD) was applied. This approach demonstrated to be useful in development of a long lasting life cycle methods. Four chromatographic variables were defined as key method parameters (KMPs) and optimized towards the analytical target profile (ATP). Designated KMPs were initial and final amount of acetonitrile in the mobile phase, pH value of the aqueous phase and gradient time, while resolutions of critical peak pairs were denoted as critical method attributes (CMAs). Relationships between KMPs and CMAs were obtained with the aid of Design of Experiments (DoEs) methodology among which Box-Behnken design (BBD) was employed to gain valid mathematical models. Obtained mathematical equations were used to construct the Design Space (DS) and select reliable optimal separation conditions. They included 11% (v/v) and 34% (v/v) of initial and final amount of acetonitrile, respectively, as well as 45 min of gradient elution time and 20 mM ammonium acetate as aqueous mobile phase with pH set to 7.35. The possibility to separate the diastereoisomers of impurity X was also evaluated. It was demonstrated that this separation could not be achieved in gradient elution mode within the defined variable domains and in a reasonable time span. The developed method was validated according to ICH Q2 (R1) guideline and met all the required criteria.
PB  - Akademiai Kiado ZRt.
T2  - Acta Chromatographica
T1  - Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach
VL  - 34
IS  - 1
SP  - 1
EP  - 11
DO  - 10.1556/1326.2021.00885
ER  - 
@article{
author = "Tomić, Jovana and Đajić, Nevena and Agbaba, Danica and Otašević, Biljana and Malenović, Anđelija and Protić, Ana",
year = "2022",
abstract = "This paper is aimed at developing a gradient elution reversed-phase high-performance liquid chromatography (RP-HPLC) method for the separation of a complex mixture composed of ivabradine and its eleven impurities, in a reasonable timeframe. In order to obtain a robust and reliable HPLC method for separation of this mixture, Analytical Quality by Design (AQbD) was applied. This approach demonstrated to be useful in development of a long lasting life cycle methods. Four chromatographic variables were defined as key method parameters (KMPs) and optimized towards the analytical target profile (ATP). Designated KMPs were initial and final amount of acetonitrile in the mobile phase, pH value of the aqueous phase and gradient time, while resolutions of critical peak pairs were denoted as critical method attributes (CMAs). Relationships between KMPs and CMAs were obtained with the aid of Design of Experiments (DoEs) methodology among which Box-Behnken design (BBD) was employed to gain valid mathematical models. Obtained mathematical equations were used to construct the Design Space (DS) and select reliable optimal separation conditions. They included 11% (v/v) and 34% (v/v) of initial and final amount of acetonitrile, respectively, as well as 45 min of gradient elution time and 20 mM ammonium acetate as aqueous mobile phase with pH set to 7.35. The possibility to separate the diastereoisomers of impurity X was also evaluated. It was demonstrated that this separation could not be achieved in gradient elution mode within the defined variable domains and in a reasonable time span. The developed method was validated according to ICH Q2 (R1) guideline and met all the required criteria.",
publisher = "Akademiai Kiado ZRt.",
journal = "Acta Chromatographica",
title = "Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach",
volume = "34",
number = "1",
pages = "1-11",
doi = "10.1556/1326.2021.00885"
}
Tomić, J., Đajić, N., Agbaba, D., Otašević, B., Malenović, A.,& Protić, A.. (2022). Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach. in Acta Chromatographica
Akademiai Kiado ZRt.., 34(1), 1-11.
https://doi.org/10.1556/1326.2021.00885
Tomić J, Đajić N, Agbaba D, Otašević B, Malenović A, Protić A. Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach. in Acta Chromatographica. 2022;34(1):1-11.
doi:10.1556/1326.2021.00885 .
Tomić, Jovana, Đajić, Nevena, Agbaba, Danica, Otašević, Biljana, Malenović, Anđelija, Protić, Ana, "Robust optimization of gradient RP HPLC method for simultaneous determination of ivabradine and its eleven related substances by AQbD approach" in Acta Chromatographica, 34, no. 1 (2022):1-11,
https://doi.org/10.1556/1326.2021.00885 . .
4
3

Hydrophilic retention mechanism of imidazoline and serotonin receptor ligands in thin-layer and high-performance liquid chromatography systems

Obradović, Darija; Savić, Jelena; Joksimović, J.; Kowalska, T.; Agbaba, Danica

(Springer, 2022)

TY  - JOUR
AU  - Obradović, Darija
AU  - Savić, Jelena
AU  - Joksimović, J.
AU  - Kowalska, T.
AU  - Agbaba, Danica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4182
AB  - We investigated and compared hydrophilic retention mechanism (HILIC) of ten compounds (imidazoline and serotonin receptor ligands) in the thin-layer chromatographic (TLC) system and the high-performance liquid chromatographic (HPLC) system. The TLC and HPLC stationary phases were the chemically bonded amino (NH2) phases. In the TLC mode, the binary mobile phases were composed of acetonitrile (as the main component) and water or methanol (as the modifier). In the HPLC mode, the binary mobile phase was composed of acetonitrile (as the main component) and methanol (as the modifier). For each compound, we determined this region for which linear relationship between the retention and volume fraction of the mobile phase modifier was observed, and the retention behaviour was described by the linear solvent strength (LSS) model. With the obtained regression constant values (log k0, RM0) in mind, we selected molecular parameters influencing retention mechanism in the considered chromatographic systems. Lipophilicity plays an important role in the TLC mode with the acetonitrile‒methanol mobile phase, while geometrical characteristics of the test compounds (ring complexity, number of multiple bonds) play a predominant role in the TLC mode with the acetonitrile‒water mobile phase. It was also established that the hydrophilic mechanisms are different for the non-aqueous TLC vs. aqueous TLC systems and for the TLC vs. HPLC systems. As a result, different elution orders and separation performances can be expected for the imidazoline and serotonin receptor ligands, depending on the chromatographic system employed.
PB  - Springer
T2  - Journal of Planar Chromatography - Modern TLC
T1  - Hydrophilic retention mechanism of imidazoline and serotonin receptor ligands in thin-layer and high-performance liquid chromatography systems
VL  - 35
IS  - 3
SP  - 251
EP  - 263
DO  - 10.1007/s00764-022-00172-6
ER  - 
@article{
author = "Obradović, Darija and Savić, Jelena and Joksimović, J. and Kowalska, T. and Agbaba, Danica",
year = "2022",
abstract = "We investigated and compared hydrophilic retention mechanism (HILIC) of ten compounds (imidazoline and serotonin receptor ligands) in the thin-layer chromatographic (TLC) system and the high-performance liquid chromatographic (HPLC) system. The TLC and HPLC stationary phases were the chemically bonded amino (NH2) phases. In the TLC mode, the binary mobile phases were composed of acetonitrile (as the main component) and water or methanol (as the modifier). In the HPLC mode, the binary mobile phase was composed of acetonitrile (as the main component) and methanol (as the modifier). For each compound, we determined this region for which linear relationship between the retention and volume fraction of the mobile phase modifier was observed, and the retention behaviour was described by the linear solvent strength (LSS) model. With the obtained regression constant values (log k0, RM0) in mind, we selected molecular parameters influencing retention mechanism in the considered chromatographic systems. Lipophilicity plays an important role in the TLC mode with the acetonitrile‒methanol mobile phase, while geometrical characteristics of the test compounds (ring complexity, number of multiple bonds) play a predominant role in the TLC mode with the acetonitrile‒water mobile phase. It was also established that the hydrophilic mechanisms are different for the non-aqueous TLC vs. aqueous TLC systems and for the TLC vs. HPLC systems. As a result, different elution orders and separation performances can be expected for the imidazoline and serotonin receptor ligands, depending on the chromatographic system employed.",
publisher = "Springer",
journal = "Journal of Planar Chromatography - Modern TLC",
title = "Hydrophilic retention mechanism of imidazoline and serotonin receptor ligands in thin-layer and high-performance liquid chromatography systems",
volume = "35",
number = "3",
pages = "251-263",
doi = "10.1007/s00764-022-00172-6"
}
Obradović, D., Savić, J., Joksimović, J., Kowalska, T.,& Agbaba, D.. (2022). Hydrophilic retention mechanism of imidazoline and serotonin receptor ligands in thin-layer and high-performance liquid chromatography systems. in Journal of Planar Chromatography - Modern TLC
Springer., 35(3), 251-263.
https://doi.org/10.1007/s00764-022-00172-6
Obradović D, Savić J, Joksimović J, Kowalska T, Agbaba D. Hydrophilic retention mechanism of imidazoline and serotonin receptor ligands in thin-layer and high-performance liquid chromatography systems. in Journal of Planar Chromatography - Modern TLC. 2022;35(3):251-263.
doi:10.1007/s00764-022-00172-6 .
Obradović, Darija, Savić, Jelena, Joksimović, J., Kowalska, T., Agbaba, Danica, "Hydrophilic retention mechanism of imidazoline and serotonin receptor ligands in thin-layer and high-performance liquid chromatography systems" in Journal of Planar Chromatography - Modern TLC, 35, no. 3 (2022):251-263,
https://doi.org/10.1007/s00764-022-00172-6 . .

Characterization of unknown degradant of ziprasidone with NMR spetroscopy

Čarapić, Marija; Petković, Miloš; Marković, Bojan; Popović-Nikolić, Marija; Agbaba, Danica; Nikolić, Katarina

(Society of Physical Chemists of Serbia, 2022)

TY  - CONF
AU  - Čarapić, Marija
AU  - Petković, Miloš
AU  - Marković, Bojan
AU  - Popović-Nikolić, Marija
AU  - Agbaba, Danica
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4684
AB  - Ziprasidone (ZIP) is the second generation antipsychotic drug with unique G-protein-coupled
(GPCR) receptor binding profile. It is a highly lipophilic and unstable compound. Our group
developed and validated the single liquid chromatographic (LC) system for simultaneous
determination of ZIP and its five main impurities (IMPs) and we modelled the Quantitative
Structure Retention Relationship (QSRR) of the additional ten compounds including unknown
detected degradant. One of two proposed structures were confirmed by UPLC-MS/MS study. The
further characterisation of unknown degradant was performed with NMR studies as un versatile
tool for characterisation of each compound and it is presented. Through several experiments which consists of investigation of chemical shitfs in NMR spectra of ZIP degradation products the
structure of unknown degradant was proposed and confirmed as in previous experiments.
PB  - Society of Physical Chemists of Serbia
C3  - PHYSICAL CHEMISTRY 2022, 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry (Proceedings)
T1  - Characterization of unknown degradant of ziprasidone with NMR spetroscopy
VL  - II
SP  - 601
EP  - 604
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4684
ER  - 
@conference{
author = "Čarapić, Marija and Petković, Miloš and Marković, Bojan and Popović-Nikolić, Marija and Agbaba, Danica and Nikolić, Katarina",
year = "2022",
abstract = "Ziprasidone (ZIP) is the second generation antipsychotic drug with unique G-protein-coupled
(GPCR) receptor binding profile. It is a highly lipophilic and unstable compound. Our group
developed and validated the single liquid chromatographic (LC) system for simultaneous
determination of ZIP and its five main impurities (IMPs) and we modelled the Quantitative
Structure Retention Relationship (QSRR) of the additional ten compounds including unknown
detected degradant. One of two proposed structures were confirmed by UPLC-MS/MS study. The
further characterisation of unknown degradant was performed with NMR studies as un versatile
tool for characterisation of each compound and it is presented. Through several experiments which consists of investigation of chemical shitfs in NMR spectra of ZIP degradation products the
structure of unknown degradant was proposed and confirmed as in previous experiments.",
publisher = "Society of Physical Chemists of Serbia",
journal = "PHYSICAL CHEMISTRY 2022, 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry (Proceedings)",
title = "Characterization of unknown degradant of ziprasidone with NMR spetroscopy",
volume = "II",
pages = "601-604",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4684"
}
Čarapić, M., Petković, M., Marković, B., Popović-Nikolić, M., Agbaba, D.,& Nikolić, K.. (2022). Characterization of unknown degradant of ziprasidone with NMR spetroscopy. in PHYSICAL CHEMISTRY 2022, 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry (Proceedings)
Society of Physical Chemists of Serbia., II, 601-604.
https://hdl.handle.net/21.15107/rcub_farfar_4684
Čarapić M, Petković M, Marković B, Popović-Nikolić M, Agbaba D, Nikolić K. Characterization of unknown degradant of ziprasidone with NMR spetroscopy. in PHYSICAL CHEMISTRY 2022, 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry (Proceedings). 2022;II:601-604.
https://hdl.handle.net/21.15107/rcub_farfar_4684 .
Čarapić, Marija, Petković, Miloš, Marković, Bojan, Popović-Nikolić, Marija, Agbaba, Danica, Nikolić, Katarina, "Characterization of unknown degradant of ziprasidone with NMR spetroscopy" in PHYSICAL CHEMISTRY 2022, 16th International Conference on Fundamental and Applied Aspects of Physical Chemistry (Proceedings), II (2022):601-604,
https://hdl.handle.net/21.15107/rcub_farfar_4684 .

Characterisation of novel impurity of ziprasidone with NMR spectroscopy and UPLC-MS/MS

Čarapić, Marija; Marković, Bojan; Petković, Miloš; Nikolić, Katarina; Agbaba, Danica

(European Research Network on Signal Transduction CA18133, 2022)

TY  - CONF
AU  - Čarapić, Marija
AU  - Marković, Bojan
AU  - Petković, Miloš
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4741
PB  - European Research Network on Signal Transduction CA18133
C3  - 2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event
T1  - Characterisation of novel impurity of ziprasidone with NMR spectroscopy and UPLC-MS/MS
SP  - 74
EP  - 74
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4741
ER  - 
@conference{
author = "Čarapić, Marija and Marković, Bojan and Petković, Miloš and Nikolić, Katarina and Agbaba, Danica",
year = "2022",
publisher = "European Research Network on Signal Transduction CA18133",
journal = "2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event",
title = "Characterisation of novel impurity of ziprasidone with NMR spectroscopy and UPLC-MS/MS",
pages = "74-74",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4741"
}
Čarapić, M., Marković, B., Petković, M., Nikolić, K.,& Agbaba, D.. (2022). Characterisation of novel impurity of ziprasidone with NMR spectroscopy and UPLC-MS/MS. in 2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event
European Research Network on Signal Transduction CA18133., 74-74.
https://hdl.handle.net/21.15107/rcub_farfar_4741
Čarapić M, Marković B, Petković M, Nikolić K, Agbaba D. Characterisation of novel impurity of ziprasidone with NMR spectroscopy and UPLC-MS/MS. in 2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event. 2022;:74-74.
https://hdl.handle.net/21.15107/rcub_farfar_4741 .
Čarapić, Marija, Marković, Bojan, Petković, Miloš, Nikolić, Katarina, Agbaba, Danica, "Characterisation of novel impurity of ziprasidone with NMR spectroscopy and UPLC-MS/MS" in 2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event (2022):74-74,
https://hdl.handle.net/21.15107/rcub_farfar_4741 .

The ANN-QSRR modeling of chromatographic properties of ziprasidone and its impurities

Čarapić, Marija; Nikolić, Katarina; Agbaba, Danica

(European Research Network on Signal Transduction CA18133, 2022)

TY  - CONF
AU  - Čarapić, Marija
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4740
PB  - European Research Network on Signal Transduction CA18133
C3  - 2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event
T1  - The ANN-QSRR modeling of chromatographic properties of ziprasidone and its impurities
SP  - 48
EP  - 48
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4740
ER  - 
@conference{
author = "Čarapić, Marija and Nikolić, Katarina and Agbaba, Danica",
year = "2022",
publisher = "European Research Network on Signal Transduction CA18133",
journal = "2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event",
title = "The ANN-QSRR modeling of chromatographic properties of ziprasidone and its impurities",
pages = "48-48",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4740"
}
Čarapić, M., Nikolić, K.,& Agbaba, D.. (2022). The ANN-QSRR modeling of chromatographic properties of ziprasidone and its impurities. in 2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event
European Research Network on Signal Transduction CA18133., 48-48.
https://hdl.handle.net/21.15107/rcub_farfar_4740
Čarapić M, Nikolić K, Agbaba D. The ANN-QSRR modeling of chromatographic properties of ziprasidone and its impurities. in 2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event. 2022;:48-48.
https://hdl.handle.net/21.15107/rcub_farfar_4740 .
Čarapić, Marija, Nikolić, Katarina, Agbaba, Danica, "The ANN-QSRR modeling of chromatographic properties of ziprasidone and its impurities" in 2nd Transatlantic ECI GPCR Symposium - Early Career Investigators – July 6-7, 2022, Online event (2022):48-48,
https://hdl.handle.net/21.15107/rcub_farfar_4740 .

Investigation of retention characteristics and an unknown degradant of ziprasidone, antipsychotic with unique profile binding for GPCRs receptor

Čarapić, Marija; Nikolić, Katarina; Agbaba, Danica

(European Research Network on Signal Transduction CA18133, 2022)

TY  - CONF
AU  - Čarapić, Marija
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4736
PB  - European Research Network on Signal Transduction CA18133
C3  - 6th ERNEST Meeting, Building a Comprehensive Map of GPCR Signal Transduction, 28-31 March, 2022.
T1  - Investigation of retention characteristics and an unknown degradant of ziprasidone, antipsychotic with unique profile binding for GPCRs receptor
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4736
ER  - 
@conference{
author = "Čarapić, Marija and Nikolić, Katarina and Agbaba, Danica",
year = "2022",
publisher = "European Research Network on Signal Transduction CA18133",
journal = "6th ERNEST Meeting, Building a Comprehensive Map of GPCR Signal Transduction, 28-31 March, 2022.",
title = "Investigation of retention characteristics and an unknown degradant of ziprasidone, antipsychotic with unique profile binding for GPCRs receptor",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4736"
}
Čarapić, M., Nikolić, K.,& Agbaba, D.. (2022). Investigation of retention characteristics and an unknown degradant of ziprasidone, antipsychotic with unique profile binding for GPCRs receptor. in 6th ERNEST Meeting, Building a Comprehensive Map of GPCR Signal Transduction, 28-31 March, 2022.
European Research Network on Signal Transduction CA18133..
https://hdl.handle.net/21.15107/rcub_farfar_4736
Čarapić M, Nikolić K, Agbaba D. Investigation of retention characteristics and an unknown degradant of ziprasidone, antipsychotic with unique profile binding for GPCRs receptor. in 6th ERNEST Meeting, Building a Comprehensive Map of GPCR Signal Transduction, 28-31 March, 2022.. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4736 .
Čarapić, Marija, Nikolić, Katarina, Agbaba, Danica, "Investigation of retention characteristics and an unknown degradant of ziprasidone, antipsychotic with unique profile binding for GPCRs receptor" in 6th ERNEST Meeting, Building a Comprehensive Map of GPCR Signal Transduction, 28-31 March, 2022. (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4736 .

New regulatory requirements in revision of ICH Q2(R2) guideline on the validation of analytical procedures

Čarapić, Marija; Vojvodić, Ljiljana; Nikolić, Katarina; Agbaba, Danica

(Savez farmaceutskih udruženja Srbije (SFUS), 2022)

TY  - CONF
AU  - Čarapić, Marija
AU  - Vojvodić, Ljiljana
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4601
AB  - Guideline ICHQ2(R1) (June 1995) provides general recommendations about
performing the validation of standard analytical procedures (HPLC/TLC/GC) used for testing
the active substance (AS)/finished product in order to show that the method is suitable for
its intended use (ensuring the quality of the medicine). The development of a new guideline
ICHQ14 Analytical procedure development is underway, which consequently led to a revision
of the guideline ICHQ2 in the R2 version (comments until July 2022). The aim of this paper is
to present an overview of new regulatory elements that should be considered during the
validation of the analytical procedure. In relation to R1, ICHQ2(R2) provides
recommendations for performing/evaluating various validation tests taking into account the
specificity of each analytical procedure. Validation principles covering the use of
spectroscopic/spectrometric data (e.g. NIR/Raman/NMR/MS) are described, some of which
often require multivariate statistical analyzes. Guideline-R1 referred to the most frequently
tested specification/process parameters (identification, testing of impurities
quantitatively/limit test, assay (1,2)). R2 describes the methodology for performing
validation for testing: elemental impurities (ICP-OES/ICP-MS), genotoxic impurities (LC/MS),
dissolution testing (HPLC), particle size determination, core tablet assay by NIR (e.g. in
continuous manufacturing), quantitative 1 H-NMR for the assay of AS. The validation
methodology used in specific tests for biological/biotechnological drugs for biological assay
(ELISA, SPR) and impurity testing-quantitative PCR, is also described. If scientifically
justified, relevant data from development studies (ICHQ14) can be used instead of validation
or the validation process can be abbreviated when an already established platform analytical
procedure is used for a new purpose.
AB  - Smernica ICHQ2(R1) (jun 1995.) daje opšte preporuke o načinu izvođenja validacije
standardnih analitičkih metoda (HPLC/TLC/GC) koje se koriste za ispitivanje aktivne
supstance (AS) i gotovog proizvoda što ima za cilj da pokaže da je metoda pogodna za
predviđenu svrhu (obezbeđenje kvaliteta leka). U toku je razvoj nove smernice ICHQ14 o
razvoju analitičkih metoda što je posledično dovelo do revizije smernice ICHQ2 u verziju R2
(na javnoj raspravi do jula 2022.). Cilj ovog rada je da se prikaže pregled novih regulatornih
elemenata koje treba razmatrati u toku validacije analitičke procedure. U odnosu na R1,
ICHQ2(R2) daje preporuke za izvođenje i procenu različitih testova validacije uzimajući u
obzir specifičnost svake analitičke procedure. Biće opisani postupci validacije koji pokrivaju
upotrebu spektroskopskih/spektrometrijskih podataka (npr. NIR, Raman, NMR ili MS) od
kojih neki često zahtevaju multivarijantne statističke analize. Smernica-R1 se odnosila na
najčešće ispitivane specifikacijske/procesne parametre (identifikacija, ispitivanje nečistoća
kvantitativno/limit test, sadržaj AS (1,2)). Verzija R2 opisuje metodologiju izvođenja
validacije za ispitivanje elelmentalnih nečistoća (ICP-OES/ICP-MS), ispitivanje genotoksičnih
nečistoća - LC/MS, ispitivanja brzine oslobađanja aktivne supstance-HPLC, određivanje
veličine čestica, validacija NIR metode za ispitivanje sadržaja AS u tabletnom jezgru (npr. kod
kontinuirane proizvodnje), validacija H-NMR za određivanje sadržaja AS. Opisana je i
validaciona metodologija koja se primenjuje kod spefičnih testova za biološke/biotehnološke
lekove za određivanje sadržaja AS (ELISA, SPR) i ispitivanje nečistoća-PCR. Ako je to
naučno opravdano, odgovarajući podaci dobijeni iz razvojnih studija (ICHQ14)
mogu se koristiti umesto validacije ili postupak validacije može biti skraćen kada
se već utvrđena platforma analitičke procedure koristi u novu svrhu.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - New regulatory requirements in revision of ICH Q2(R2) guideline on the validation of analytical procedures
T1  - Novi regulatorni zahtevi u reviziji ICH Q2 smernice o validaciji analitičkih metoda
VL  - 72
IS  - 4 suplement
SP  - S538
EP  - S539
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4601
ER  - 
@conference{
author = "Čarapić, Marija and Vojvodić, Ljiljana and Nikolić, Katarina and Agbaba, Danica",
year = "2022",
abstract = "Guideline ICHQ2(R1) (June 1995) provides general recommendations about
performing the validation of standard analytical procedures (HPLC/TLC/GC) used for testing
the active substance (AS)/finished product in order to show that the method is suitable for
its intended use (ensuring the quality of the medicine). The development of a new guideline
ICHQ14 Analytical procedure development is underway, which consequently led to a revision
of the guideline ICHQ2 in the R2 version (comments until July 2022). The aim of this paper is
to present an overview of new regulatory elements that should be considered during the
validation of the analytical procedure. In relation to R1, ICHQ2(R2) provides
recommendations for performing/evaluating various validation tests taking into account the
specificity of each analytical procedure. Validation principles covering the use of
spectroscopic/spectrometric data (e.g. NIR/Raman/NMR/MS) are described, some of which
often require multivariate statistical analyzes. Guideline-R1 referred to the most frequently
tested specification/process parameters (identification, testing of impurities
quantitatively/limit test, assay (1,2)). R2 describes the methodology for performing
validation for testing: elemental impurities (ICP-OES/ICP-MS), genotoxic impurities (LC/MS),
dissolution testing (HPLC), particle size determination, core tablet assay by NIR (e.g. in
continuous manufacturing), quantitative 1 H-NMR for the assay of AS. The validation
methodology used in specific tests for biological/biotechnological drugs for biological assay
(ELISA, SPR) and impurity testing-quantitative PCR, is also described. If scientifically
justified, relevant data from development studies (ICHQ14) can be used instead of validation
or the validation process can be abbreviated when an already established platform analytical
procedure is used for a new purpose., Smernica ICHQ2(R1) (jun 1995.) daje opšte preporuke o načinu izvođenja validacije
standardnih analitičkih metoda (HPLC/TLC/GC) koje se koriste za ispitivanje aktivne
supstance (AS) i gotovog proizvoda što ima za cilj da pokaže da je metoda pogodna za
predviđenu svrhu (obezbeđenje kvaliteta leka). U toku je razvoj nove smernice ICHQ14 o
razvoju analitičkih metoda što je posledično dovelo do revizije smernice ICHQ2 u verziju R2
(na javnoj raspravi do jula 2022.). Cilj ovog rada je da se prikaže pregled novih regulatornih
elemenata koje treba razmatrati u toku validacije analitičke procedure. U odnosu na R1,
ICHQ2(R2) daje preporuke za izvođenje i procenu različitih testova validacije uzimajući u
obzir specifičnost svake analitičke procedure. Biće opisani postupci validacije koji pokrivaju
upotrebu spektroskopskih/spektrometrijskih podataka (npr. NIR, Raman, NMR ili MS) od
kojih neki često zahtevaju multivarijantne statističke analize. Smernica-R1 se odnosila na
najčešće ispitivane specifikacijske/procesne parametre (identifikacija, ispitivanje nečistoća
kvantitativno/limit test, sadržaj AS (1,2)). Verzija R2 opisuje metodologiju izvođenja
validacije za ispitivanje elelmentalnih nečistoća (ICP-OES/ICP-MS), ispitivanje genotoksičnih
nečistoća - LC/MS, ispitivanja brzine oslobađanja aktivne supstance-HPLC, određivanje
veličine čestica, validacija NIR metode za ispitivanje sadržaja AS u tabletnom jezgru (npr. kod
kontinuirane proizvodnje), validacija H-NMR za određivanje sadržaja AS. Opisana je i
validaciona metodologija koja se primenjuje kod spefičnih testova za biološke/biotehnološke
lekove za određivanje sadržaja AS (ELISA, SPR) i ispitivanje nečistoća-PCR. Ako je to
naučno opravdano, odgovarajući podaci dobijeni iz razvojnih studija (ICHQ14)
mogu se koristiti umesto validacije ili postupak validacije može biti skraćen kada
se već utvrđena platforma analitičke procedure koristi u novu svrhu.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "New regulatory requirements in revision of ICH Q2(R2) guideline on the validation of analytical procedures, Novi regulatorni zahtevi u reviziji ICH Q2 smernice o validaciji analitičkih metoda",
volume = "72",
number = "4 suplement",
pages = "S538-S539",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4601"
}
Čarapić, M., Vojvodić, L., Nikolić, K.,& Agbaba, D.. (2022). New regulatory requirements in revision of ICH Q2(R2) guideline on the validation of analytical procedures. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S538-S539.
https://hdl.handle.net/21.15107/rcub_farfar_4601
Čarapić M, Vojvodić L, Nikolić K, Agbaba D. New regulatory requirements in revision of ICH Q2(R2) guideline on the validation of analytical procedures. in Arhiv za farmaciju. 2022;72(4 suplement):S538-S539.
https://hdl.handle.net/21.15107/rcub_farfar_4601 .
Čarapić, Marija, Vojvodić, Ljiljana, Nikolić, Katarina, Agbaba, Danica, "New regulatory requirements in revision of ICH Q2(R2) guideline on the validation of analytical procedures" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S538-S539,
https://hdl.handle.net/21.15107/rcub_farfar_4601 .

Development and validation of UHPLC-MS/MS method for analysis of ziprasidone and its impurities

Čarapić, Marija; Marković, Bojan; Nikolić, Katarina; Agbaba, Danica

(Savez farmaceutskih udruženja Srbije (SFUS), 2022)

TY  - CONF
AU  - Čarapić, Marija
AU  - Marković, Bojan
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4600
AB  - Ziprasidone, bensiothiasol piperazynylindolone derivative is second generation
antipsychotic drug used for the treatment of schizophrenia and in acute maniac/mixed
episodes associated with bipolar disorder. It has unique G-protein coupled receptor binding
profile with relatively low propensity for weight gain (1). Recently, it became an official
active pharmaceutical ingredient in European Pharmacopoeia, where there are three official
chromatographic systems, one for the assay and two other for early-eluiting and late-eluting
impurities. Therefore, the purpose of this investigation was to develop and validate a fast,
highly sensitive UHPLC-MS/MS method for the analysis of ziprasidone and its five impurities,
significantly differing in polarity and pKa. Separation was performed using Thermo ACCELA
UHPLC system (Thermo Scientific, Waltham, MA, USA) equipped with triple quad Mass
Spectrometer Thermo TSQ Quantum Access Max (Thermo Scientific, Waltham, MA, USA)
with a heated electro-spray ionization interface. Satisfactory chromatographic separation
was achieved using a gradient elution with mobile phase A (10mM ammonium formate
buffer, pH 4.7) and mobile phase B (acetonitrile) on a Acquity UPLC BEH C18 (50×2.1 mm,
1.7 μm) column with mobile phase flow rate of 300 μL/min. Sample injection volume was 10
μL. The analysis runtime was 7 minutes. The method was validated according to the
International Conference of Harmonization (ICH) guidelines and validation included
parameters such as specificity, linearity, accuracy, precision, limit of quantification and limit
of detection. The proposed rapid and sensitive method is convenient and reliable for the
assay and purity control in raw materials and in dosage forms (2).
AB  - Ziprasidon, derivat benzizotiazol piperazinilindolona, je antipsihotik druge generacije
koji se koristi za lečenje šizofrenije, kod akutnih maničnih ili mešovitih epizoda povezanih sa
bipolarnim poremećajem. Ima jedinstveni profil vezivanja za G protein-spregnute receptore
(GPCR) i relativno retko neželjeno dejstvo povećanja telesne težine (1). Nedavno je
monografija dve soli ziprasidona postala oficinalna u Evropskoj farmakopeji u kojoj se
ispitivanje vrši pomoću tri hromatografska sistema: ispitivanje sadržaja i dva odvojena
sistema za više i manje polarne nečistoće. Svrha ovog istraživanja bila da se razvije i validira
brza i visoko osetljiva UHPLC-MS/MS metoda za istovremeno ispitivanje ziprasidona i
njegovih pet nečistoća, koje se značajno razlikuju po polarnosti i pKa. Hromatografska
analiza je vršena na Thermo ACCELA UHPLC sistemu koji je spregnut sa tripl kvadrupolskim
masenim analizatorom Thermo TSQ Quantum Access Max (Thermo Scientific, Valtham, MA,
USA) sa elektrosprej jonizacijom na povišenoj temperaturi (HESI) kao jonskim izvorom.
Zadovoljavajuće razdvajanje dobijeno je korišć enjem gradijentog eluiranja sa mobilnom
fazom A (10 mM amonijum-formijat, pH 4,7) i mobilnom fazom B (acetonitril) na Acquity
UPLC BEH 50×2,1 mm, 1,7 μm (Waters) stacionarnoj fazi na temperaturi od 30ºC i pri
protoku mobilne faze od 300 μL/min. Zapremina injektovanja ispitivanih rastvora bila je
10 μL. Trajanje analize je 7 minuta (2). Metoda je validirana u skladu sa ICH (International
Council for Harmonisation) smernicom i pokazana je specifičnost metode, linearnost,
tačnost, preciznost, limit kvantifikacije i limit detekcije. Potvrđeno je da se brza i osetljiva
UHPLC-MS/MS metoda može primeniti za ispitivanje ziprasidona i njegovih nečistoća u
aktivnoj supstanci i doziranim oblicima.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Development and validation of UHPLC-MS/MS method for analysis of ziprasidone and its impurities
T1  - Razvoj i validacija UHPLC‐MS/MS metode za ispitivanje ziprasidona i njegovih nečistoća
VL  - 72
IS  - 4 suplement
SP  - S536
EP  - S537
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4600
ER  - 
@conference{
author = "Čarapić, Marija and Marković, Bojan and Nikolić, Katarina and Agbaba, Danica",
year = "2022",
abstract = "Ziprasidone, bensiothiasol piperazynylindolone derivative is second generation
antipsychotic drug used for the treatment of schizophrenia and in acute maniac/mixed
episodes associated with bipolar disorder. It has unique G-protein coupled receptor binding
profile with relatively low propensity for weight gain (1). Recently, it became an official
active pharmaceutical ingredient in European Pharmacopoeia, where there are three official
chromatographic systems, one for the assay and two other for early-eluiting and late-eluting
impurities. Therefore, the purpose of this investigation was to develop and validate a fast,
highly sensitive UHPLC-MS/MS method for the analysis of ziprasidone and its five impurities,
significantly differing in polarity and pKa. Separation was performed using Thermo ACCELA
UHPLC system (Thermo Scientific, Waltham, MA, USA) equipped with triple quad Mass
Spectrometer Thermo TSQ Quantum Access Max (Thermo Scientific, Waltham, MA, USA)
with a heated electro-spray ionization interface. Satisfactory chromatographic separation
was achieved using a gradient elution with mobile phase A (10mM ammonium formate
buffer, pH 4.7) and mobile phase B (acetonitrile) on a Acquity UPLC BEH C18 (50×2.1 mm,
1.7 μm) column with mobile phase flow rate of 300 μL/min. Sample injection volume was 10
μL. The analysis runtime was 7 minutes. The method was validated according to the
International Conference of Harmonization (ICH) guidelines and validation included
parameters such as specificity, linearity, accuracy, precision, limit of quantification and limit
of detection. The proposed rapid and sensitive method is convenient and reliable for the
assay and purity control in raw materials and in dosage forms (2)., Ziprasidon, derivat benzizotiazol piperazinilindolona, je antipsihotik druge generacije
koji se koristi za lečenje šizofrenije, kod akutnih maničnih ili mešovitih epizoda povezanih sa
bipolarnim poremećajem. Ima jedinstveni profil vezivanja za G protein-spregnute receptore
(GPCR) i relativno retko neželjeno dejstvo povećanja telesne težine (1). Nedavno je
monografija dve soli ziprasidona postala oficinalna u Evropskoj farmakopeji u kojoj se
ispitivanje vrši pomoću tri hromatografska sistema: ispitivanje sadržaja i dva odvojena
sistema za više i manje polarne nečistoće. Svrha ovog istraživanja bila da se razvije i validira
brza i visoko osetljiva UHPLC-MS/MS metoda za istovremeno ispitivanje ziprasidona i
njegovih pet nečistoća, koje se značajno razlikuju po polarnosti i pKa. Hromatografska
analiza je vršena na Thermo ACCELA UHPLC sistemu koji je spregnut sa tripl kvadrupolskim
masenim analizatorom Thermo TSQ Quantum Access Max (Thermo Scientific, Valtham, MA,
USA) sa elektrosprej jonizacijom na povišenoj temperaturi (HESI) kao jonskim izvorom.
Zadovoljavajuće razdvajanje dobijeno je korišć enjem gradijentog eluiranja sa mobilnom
fazom A (10 mM amonijum-formijat, pH 4,7) i mobilnom fazom B (acetonitril) na Acquity
UPLC BEH 50×2,1 mm, 1,7 μm (Waters) stacionarnoj fazi na temperaturi od 30ºC i pri
protoku mobilne faze od 300 μL/min. Zapremina injektovanja ispitivanih rastvora bila je
10 μL. Trajanje analize je 7 minuta (2). Metoda je validirana u skladu sa ICH (International
Council for Harmonisation) smernicom i pokazana je specifičnost metode, linearnost,
tačnost, preciznost, limit kvantifikacije i limit detekcije. Potvrđeno je da se brza i osetljiva
UHPLC-MS/MS metoda može primeniti za ispitivanje ziprasidona i njegovih nečistoća u
aktivnoj supstanci i doziranim oblicima.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Development and validation of UHPLC-MS/MS method for analysis of ziprasidone and its impurities, Razvoj i validacija UHPLC‐MS/MS metode za ispitivanje ziprasidona i njegovih nečistoća",
volume = "72",
number = "4 suplement",
pages = "S536-S537",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4600"
}
Čarapić, M., Marković, B., Nikolić, K.,& Agbaba, D.. (2022). Development and validation of UHPLC-MS/MS method for analysis of ziprasidone and its impurities. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S536-S537.
https://hdl.handle.net/21.15107/rcub_farfar_4600
Čarapić M, Marković B, Nikolić K, Agbaba D. Development and validation of UHPLC-MS/MS method for analysis of ziprasidone and its impurities. in Arhiv za farmaciju. 2022;72(4 suplement):S536-S537.
https://hdl.handle.net/21.15107/rcub_farfar_4600 .
Čarapić, Marija, Marković, Bojan, Nikolić, Katarina, Agbaba, Danica, "Development and validation of UHPLC-MS/MS method for analysis of ziprasidone and its impurities" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S536-S537,
https://hdl.handle.net/21.15107/rcub_farfar_4600 .

Genotoxic impurities in medicinal products – regulatory requirements

Čarapić, Marija; Nikolić, Katarina; Agbaba, Danica

(Savez farmaceutskih udruženja Srbije (SFUS), 2022)

TY  - CONF
AU  - Čarapić, Marija
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4476
AB  - Most chemical syntheses use highly reactive molecules, which are often DNA-reactive
(mutagens). They may be present in the active substance (AS) or in the drug product as
genotoxic impurities (GI). The mechanism of action of most GIs is based on DNA modification
by direct binding (electrophilic - alkylating agents), insertion into the DNA chain
(topoisomerase inhibitors) and antimetabolites (purine/pyrimidine analogs). Structural
alerts (SA) for carcinogenic activity are defined as functional groups or substructures of
compounds associated with carcinogenic activity (1). SA indicates a chemical group that causes
toxic effects through one or several common mechanisms of action. GIs can bind directly to DNA
or after metabolic transformations (oxidation and reduction), thus the SA structure may indicate
the formation of several toxic metabolites. The risk assessment for the presence of GIs is a
mandatory part in the module 3 (AS/DP impurity profile) submitted in the marketing authorization
procedure, also in the approval of clinical trials. Guideline ICHM7(2) provides recommendations
for identification, categorization, qualification and control strategy of mutagenic impurities in
order to limit the potential carcinogenic risk. According to ICHM7, the classification (class 1-5) of
all impurities is performed on the basis of data on carcinogenicity and bacterial mutagenicity (BM)
from databases/scientific literature. If data are not available, computational toxicological
assessment (QSAR) is performed and BM is predicted with two independent models. If any of
model shows SA structures, a BM assay (Ames test) is performed. The high potent mutagenic
carcinogens (aflatoxins, nitrosamines, alkyl-azoxy compounds) referred to as “cohort of concern”.
AB  - U većini hemijskih sinteza se koriste veoma reaktivni molekuli koji su često i DNK –
reaktivni (mutageni). Oni mogu biti prisutni u aktivnoj supstanci (AS) ili gotovom proizvodu
(GP) kao genotoksične nečistoće (GN). Mehanizam dejstva većine GN se zasniva na
modifikaciji DNK i to direktnim vezivanjem (elektrofili - alkilujući agensi), umetanjem u
lanac DNK (inhibitori topoizomeraze) i antimetaboliti (purinski/pirimidinski analozi).
Upozoravajuće strukture (SA) za kancerogenu aktivnost se definišu kao funkcionalne grupe
ili delovi strukture jedinjenja koje su povezane sa kancerogenom aktivnošću (1). SA ukazuje
na hemijsku grupu jedinjenja koja izaziva toksične efekte kroz jedan ili nekoliko obično
zajedničkih mehanizama delovanja. GN mogu direktno da se vezuju za DNK ili nakon
metaboličkih transformacija (oksidacija i redukcija) pa SA struktura može da ukaže na
nastanak nekoliko toksičnih metabolita. Procena rizika na prisustvo GN u delu koji se odnosi
na profil nečistoća AS/GP je obavezan deo dokumentacije o kvalitetu leka koji se podnosi u
postupku registracije leka, kao i odobravanja kliničkih ispitivanja. U smernici ICHM7(2) su
date preporuke za identifikaciju, kategorizaciju, kvalifikaciju i kontrolnu strategiju
mutagenih nečistoća kako bi se ograničio potencijalni kancerogeni rizik. Prema ICHM7 se
vrši klasifikacija (klase 1-5) svih nečistoća na osnovu podataka o kancerogenosti i
bakterijskoj mutagenosti iz baza i naučne literature. Ako podaci nisu dostupni sprovodi se in
silico toksikološka procena (QSAR) i predviđa se bakterijska mutagenost sa dva nezavisna
modela. Ako jedan od modela pokaže SA strukture, radi se test povratne mutacije na
bakterijama (Ames test). Posebno se razmatraju visoko potentni mutageni kancerogeni
(aflatoksini, nitrozamini, alkil-azoksi jedinjenja).
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Genotoxic impurities in medicinal products – regulatory requirements
T1  - Genotoksične nečistoće u lekovima ‐ regulatorni zahtevi
VL  - 72
IS  - 4 suplement
SP  - S133
EP  - S134
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4476
ER  - 
@conference{
author = "Čarapić, Marija and Nikolić, Katarina and Agbaba, Danica",
year = "2022",
abstract = "Most chemical syntheses use highly reactive molecules, which are often DNA-reactive
(mutagens). They may be present in the active substance (AS) or in the drug product as
genotoxic impurities (GI). The mechanism of action of most GIs is based on DNA modification
by direct binding (electrophilic - alkylating agents), insertion into the DNA chain
(topoisomerase inhibitors) and antimetabolites (purine/pyrimidine analogs). Structural
alerts (SA) for carcinogenic activity are defined as functional groups or substructures of
compounds associated with carcinogenic activity (1). SA indicates a chemical group that causes
toxic effects through one or several common mechanisms of action. GIs can bind directly to DNA
or after metabolic transformations (oxidation and reduction), thus the SA structure may indicate
the formation of several toxic metabolites. The risk assessment for the presence of GIs is a
mandatory part in the module 3 (AS/DP impurity profile) submitted in the marketing authorization
procedure, also in the approval of clinical trials. Guideline ICHM7(2) provides recommendations
for identification, categorization, qualification and control strategy of mutagenic impurities in
order to limit the potential carcinogenic risk. According to ICHM7, the classification (class 1-5) of
all impurities is performed on the basis of data on carcinogenicity and bacterial mutagenicity (BM)
from databases/scientific literature. If data are not available, computational toxicological
assessment (QSAR) is performed and BM is predicted with two independent models. If any of
model shows SA structures, a BM assay (Ames test) is performed. The high potent mutagenic
carcinogens (aflatoxins, nitrosamines, alkyl-azoxy compounds) referred to as “cohort of concern”., U većini hemijskih sinteza se koriste veoma reaktivni molekuli koji su često i DNK –
reaktivni (mutageni). Oni mogu biti prisutni u aktivnoj supstanci (AS) ili gotovom proizvodu
(GP) kao genotoksične nečistoće (GN). Mehanizam dejstva većine GN se zasniva na
modifikaciji DNK i to direktnim vezivanjem (elektrofili - alkilujući agensi), umetanjem u
lanac DNK (inhibitori topoizomeraze) i antimetaboliti (purinski/pirimidinski analozi).
Upozoravajuće strukture (SA) za kancerogenu aktivnost se definišu kao funkcionalne grupe
ili delovi strukture jedinjenja koje su povezane sa kancerogenom aktivnošću (1). SA ukazuje
na hemijsku grupu jedinjenja koja izaziva toksične efekte kroz jedan ili nekoliko obično
zajedničkih mehanizama delovanja. GN mogu direktno da se vezuju za DNK ili nakon
metaboličkih transformacija (oksidacija i redukcija) pa SA struktura može da ukaže na
nastanak nekoliko toksičnih metabolita. Procena rizika na prisustvo GN u delu koji se odnosi
na profil nečistoća AS/GP je obavezan deo dokumentacije o kvalitetu leka koji se podnosi u
postupku registracije leka, kao i odobravanja kliničkih ispitivanja. U smernici ICHM7(2) su
date preporuke za identifikaciju, kategorizaciju, kvalifikaciju i kontrolnu strategiju
mutagenih nečistoća kako bi se ograničio potencijalni kancerogeni rizik. Prema ICHM7 se
vrši klasifikacija (klase 1-5) svih nečistoća na osnovu podataka o kancerogenosti i
bakterijskoj mutagenosti iz baza i naučne literature. Ako podaci nisu dostupni sprovodi se in
silico toksikološka procena (QSAR) i predviđa se bakterijska mutagenost sa dva nezavisna
modela. Ako jedan od modela pokaže SA strukture, radi se test povratne mutacije na
bakterijama (Ames test). Posebno se razmatraju visoko potentni mutageni kancerogeni
(aflatoksini, nitrozamini, alkil-azoksi jedinjenja).",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Genotoxic impurities in medicinal products – regulatory requirements, Genotoksične nečistoće u lekovima ‐ regulatorni zahtevi",
volume = "72",
number = "4 suplement",
pages = "S133-S134",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4476"
}
Čarapić, M., Nikolić, K.,& Agbaba, D.. (2022). Genotoxic impurities in medicinal products – regulatory requirements. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S133-S134.
https://hdl.handle.net/21.15107/rcub_farfar_4476
Čarapić M, Nikolić K, Agbaba D. Genotoxic impurities in medicinal products – regulatory requirements. in Arhiv za farmaciju. 2022;72(4 suplement):S133-S134.
https://hdl.handle.net/21.15107/rcub_farfar_4476 .
Čarapić, Marija, Nikolić, Katarina, Agbaba, Danica, "Genotoxic impurities in medicinal products – regulatory requirements" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S133-S134,
https://hdl.handle.net/21.15107/rcub_farfar_4476 .

Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors

Ružić, Dušan; Đoković, Nemanja; Petković, Miloš; Agbaba, Danica; Gul, Sheraz; Lahtela‐Kakkonen, Maija; Ganesan, A.; Santibanez, Juan; Srdić-Rajić, Tatjana; Nikolić, Katarina

(EFMC-ISMC, 2021)

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Gul, Sheraz
AU  - Lahtela‐Kakkonen, Maija
AU  - Ganesan, A.
AU  - Santibanez, Juan
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4889
AB  - Histone deacetylases (HDACs) are epigenetic enzymes involved in regulation of histone posttranslational
modifications and gene expression. Since changed function of HDACs is involved in pathogenesis of cancer 1-3,
the HDAC inhibitors are extensive examined as promising anticancer agents. In our in silico study we have
combined structure-based, ligand-based, and fragment-based methodologies to design selective inhibitors against
cytoplasmic isoforms of HDAC, such as histone deacetylase 6 inhibitors (HDAC6) and SIRT2. The drug design
study has defined several promising selective HDAC6 and SIRT2 inhibitors for further synthesis and in vitro
testing. Based on the in vitro activities of the novel compounds in a panel of biochemical HDAC assays as well
as various cell-based assays were selected the most promising candidates for further investigation.
PB  - EFMC-ISMC
C3  - EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
T1  - Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors
SP  - 360
EP  - 360
EP  - 
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4889
ER  - 
@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Gul, Sheraz and Lahtela‐Kakkonen, Maija and Ganesan, A. and Santibanez, Juan and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2021",
abstract = "Histone deacetylases (HDACs) are epigenetic enzymes involved in regulation of histone posttranslational
modifications and gene expression. Since changed function of HDACs is involved in pathogenesis of cancer 1-3,
the HDAC inhibitors are extensive examined as promising anticancer agents. In our in silico study we have
combined structure-based, ligand-based, and fragment-based methodologies to design selective inhibitors against
cytoplasmic isoforms of HDAC, such as histone deacetylase 6 inhibitors (HDAC6) and SIRT2. The drug design
study has defined several promising selective HDAC6 and SIRT2 inhibitors for further synthesis and in vitro
testing. Based on the in vitro activities of the novel compounds in a panel of biochemical HDAC assays as well
as various cell-based assays were selected the most promising candidates for further investigation.",
publisher = "EFMC-ISMC",
journal = "EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts",
title = "Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors",
pages = "360-360-",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4889"
}
Ružić, D., Đoković, N., Petković, M., Agbaba, D., Gul, S., Lahtela‐Kakkonen, M., Ganesan, A., Santibanez, J., Srdić-Rajić, T.,& Nikolić, K.. (2021). Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors. in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
EFMC-ISMC., 360-360.
https://hdl.handle.net/21.15107/rcub_farfar_4889
Ružić D, Đoković N, Petković M, Agbaba D, Gul S, Lahtela‐Kakkonen M, Ganesan A, Santibanez J, Srdić-Rajić T, Nikolić K. Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors. in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts. 2021;:360-360.
https://hdl.handle.net/21.15107/rcub_farfar_4889 .
Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Gul, Sheraz, Lahtela‐Kakkonen, Maija, Ganesan, A., Santibanez, Juan, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors" in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts (2021):360-360,
https://hdl.handle.net/21.15107/rcub_farfar_4889 .

QSRR Modeling of liquid chromatography separation of ziprasidone compounds

Čarapić, Marija; Nikolić, Katarina; Agbaba, Danica

(Institute for Information Technologies, University of Kragujevac, Serbia, 2021)

TY  - CONF
AU  - Čarapić, Marija
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4858
PB  - Institute for Information Technologies, University of Kragujevac, Serbia
C3  - 1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS)
T1  - QSRR Modeling of liquid chromatography separation of ziprasidone compounds
SP  - 284
EP  - 287
DO  - 10.46793/ICCBI21.284C
ER  - 
@conference{
author = "Čarapić, Marija and Nikolić, Katarina and Agbaba, Danica",
year = "2021",
publisher = "Institute for Information Technologies, University of Kragujevac, Serbia",
journal = "1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS)",
title = "QSRR Modeling of liquid chromatography separation of ziprasidone compounds",
pages = "284-287",
doi = "10.46793/ICCBI21.284C"
}
Čarapić, M., Nikolić, K.,& Agbaba, D.. (2021). QSRR Modeling of liquid chromatography separation of ziprasidone compounds. in 1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS)
Institute for Information Technologies, University of Kragujevac, Serbia., 284-287.
https://doi.org/10.46793/ICCBI21.284C
Čarapić M, Nikolić K, Agbaba D. QSRR Modeling of liquid chromatography separation of ziprasidone compounds. in 1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS). 2021;:284-287.
doi:10.46793/ICCBI21.284C .
Čarapić, Marija, Nikolić, Katarina, Agbaba, Danica, "QSRR Modeling of liquid chromatography separation of ziprasidone compounds" in 1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS) (2021):284-287,
https://doi.org/10.46793/ICCBI21.284C . .

Modeling retention behaviour of imidazoline and serotonin receptor ligands under conditions of green SFC techique

Obradović, Darija; Nikolaevich Stavrianidi, Andrey; Alekseevich Shpigun, Oleg; Agbaba, Danica

(Savez farmaceutskih udruženja Srbije (SFUS), 2021)

TY  - CONF
AU  - Obradović, Darija
AU  - Nikolaevich Stavrianidi, Andrey
AU  - Alekseevich Shpigun, Oleg
AU  - Agbaba, Danica
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4681
AB  - A possibility of predicting retention behaviour without a large number of preliminary
experiments is a significant segment of theoretical and experimental investigations. By using
an appropriate design to define experimental conditions (Design of Experiments, DoE), the
retention behaviour of compounds can be described as a function of the most important
parameters of chromatographic system. Further, the DoE methodology has shown successful
applicability to modeling retention under the environmentally friendly Supercritical Fluid
Chromatography (SFC) conditions (1). In the last decades, robustness of the SFC instruments
has been improved in order to minimize ecological risks, and routine application of the SFC
technique has been introduced into many pharmaceutical strategies (e.g., the Good
Manufacturing Practice, GMP) (2). Therefore, the aim of our study was to define the influence
of the main chromatographic factors on the retention behaviour of fourteen imidazoline and
serotonin receptor ligands under the SFC conditions. Using the Central Composite Design
(CCD) approach, retention characteristics (k) of the test compounds were examined on the
mixed-mode stationary phase, with the mixture of supercritical CO2 and methanolic
ammonium-formate (with an addition of 0.1% formic acid) used as mobile phase. We took into
the consideration the influence of the following factors: volume fraction of methanol in mobile
phase (20-30 %), ammonium-formate concentration (15-25 mM), and temperature deviation
(20-30 °C). The most important chromatographic factors were selected by the step-wise
multilinear regression (MLR), and their statistical significance was assessed using the ANOVA
analysis. Based on the results obtained, it was established that the retention characteristics
were significantly influenced by changing the methanol and ammonium-formate
concentrations in mobile phase (r > 0.90, p < 0.05), Figure 1. High degree of agreement (r >
0.98) was observed, when the theoretically predicted logk values for 35% and 15% volume
fraction of methanol in mobile phase were compared with the experimental ones. The
obtained results confirm successful applicability of the experimental design methodology in
order to perform a minimum number of experiments, as demonstrated upon an example of
modeling and predicting the retention behaviour of imidazoline and serotonin receptor
ligands under the SFC conditions.
AB  - Mogućnost predviđanja retencije u odsustvu velikog broja prethodnih eksperimenata,
značajan je segment teorijskih i eksperimentalnih ispitivanja. Odgovarajućim dizajnom
eksperimentalnih uslova (Design of Experiments, DoE), a na osnovu minimalnog broja
eksperimenata, može se definisati retenciono ponašanje jedinjenja u funkciji najznačajnijih
parametara hromatografskog sistema. Primena DoE metodologije je takođe zabeležena i
prilikom modelovanja retencije u uslovima ekološki bezbedne, superkritične fluidne
hromatografije (Supercritical Fluid Chromatography, SFC) (1). Zbog minimalnih ekoloških
rizika, robusnost SFC instrumenata je poboljšana, a rutinska primena SFC tehnike je uvedena
i u regulatorne farmaceutske propise (npr. dobra proizvođačka praksa; Good Manufacturing
Practice-GMP) (2). Na osnovu toga, cilj ovog istraživanja obuhvatio je definisanje uticaja
najznačajnijih faktora hromatografskog sistema na retenciono ponašanje 14 odabranih
liganada imidazolinskih i serotoninskih receptora na mixed-mode stacionarnoj fazi u SFC
uslovima. Uticaj zapreminskog udela metanola (20-30 %), koncentracije amonijum-formijata
(15-25 mM) i temperature (20-30 °C) na vrednosti retencionih faktora (k) odabranih liganada
imidazolinskih i serotoninskih receptora je ispitana primenom centralnog kompozitnog
dizajna (Central Composite Design, CCD) na mixed-mode stacionarnoj fazi. Kao mobilna faza
korišćena je smeša superkritičnog CO2 i metanolnog rastvora amonijum-formijata uz dodatak
0,1% mravlje kiseline. Najznačajniji hromatografski faktori su izdvojeni step-wise postupkom
u višestrukoj linearnoj regresionoj analizi (Multiple Linear Regression, MLR), a njihova
statistička značajnost je procenjena primenom ANOVA testa. U konstruisanim retencionim
modelima, zapremina metanola i koncentracija pufera su pokazale najveći uticaj na retenciono
ponašanje testiranih jedinjenja (r > 0,90; p < 0,05), Slika 1. U koliko se teorijski predviđene
logk vrednosti uporede sa eksperimentalno dobijenim vrednostima na 35% i 15%
zapreminskim udelima metanola u mobilnoj fazi, uočava se da je prisutan visok stepen
slaganja (r > 0,98). Dobijeni rezultati potvrđuju uspešnu primenljivost metodologije
eksperimentalnog dizajna u cilju izvođenja minimalnog broja eksperimenata, prilikom
modelovanja i predikcije retencionog ponašanja liganda imidazolinskih i serotoninskih
receptora u SFC sistemima.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Modeling retention behaviour of imidazoline and serotonin receptor ligands under conditions of green SFC techique
T1  - Modelovanje retencionog ponašanja liganada imidazolinskih i serotoninskih receptora u uslovima ekološki bezbedne SFC tehnike
VL  - 71
IS  - 5 suplement
SP  - S126
EP  - S129
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4681
ER  - 
@conference{
author = "Obradović, Darija and Nikolaevich Stavrianidi, Andrey and Alekseevich Shpigun, Oleg and Agbaba, Danica",
year = "2021",
abstract = "A possibility of predicting retention behaviour without a large number of preliminary
experiments is a significant segment of theoretical and experimental investigations. By using
an appropriate design to define experimental conditions (Design of Experiments, DoE), the
retention behaviour of compounds can be described as a function of the most important
parameters of chromatographic system. Further, the DoE methodology has shown successful
applicability to modeling retention under the environmentally friendly Supercritical Fluid
Chromatography (SFC) conditions (1). In the last decades, robustness of the SFC instruments
has been improved in order to minimize ecological risks, and routine application of the SFC
technique has been introduced into many pharmaceutical strategies (e.g., the Good
Manufacturing Practice, GMP) (2). Therefore, the aim of our study was to define the influence
of the main chromatographic factors on the retention behaviour of fourteen imidazoline and
serotonin receptor ligands under the SFC conditions. Using the Central Composite Design
(CCD) approach, retention characteristics (k) of the test compounds were examined on the
mixed-mode stationary phase, with the mixture of supercritical CO2 and methanolic
ammonium-formate (with an addition of 0.1% formic acid) used as mobile phase. We took into
the consideration the influence of the following factors: volume fraction of methanol in mobile
phase (20-30 %), ammonium-formate concentration (15-25 mM), and temperature deviation
(20-30 °C). The most important chromatographic factors were selected by the step-wise
multilinear regression (MLR), and their statistical significance was assessed using the ANOVA
analysis. Based on the results obtained, it was established that the retention characteristics
were significantly influenced by changing the methanol and ammonium-formate
concentrations in mobile phase (r > 0.90, p < 0.05), Figure 1. High degree of agreement (r >
0.98) was observed, when the theoretically predicted logk values for 35% and 15% volume
fraction of methanol in mobile phase were compared with the experimental ones. The
obtained results confirm successful applicability of the experimental design methodology in
order to perform a minimum number of experiments, as demonstrated upon an example of
modeling and predicting the retention behaviour of imidazoline and serotonin receptor
ligands under the SFC conditions., Mogućnost predviđanja retencije u odsustvu velikog broja prethodnih eksperimenata,
značajan je segment teorijskih i eksperimentalnih ispitivanja. Odgovarajućim dizajnom
eksperimentalnih uslova (Design of Experiments, DoE), a na osnovu minimalnog broja
eksperimenata, može se definisati retenciono ponašanje jedinjenja u funkciji najznačajnijih
parametara hromatografskog sistema. Primena DoE metodologije je takođe zabeležena i
prilikom modelovanja retencije u uslovima ekološki bezbedne, superkritične fluidne
hromatografije (Supercritical Fluid Chromatography, SFC) (1). Zbog minimalnih ekoloških
rizika, robusnost SFC instrumenata je poboljšana, a rutinska primena SFC tehnike je uvedena
i u regulatorne farmaceutske propise (npr. dobra proizvođačka praksa; Good Manufacturing
Practice-GMP) (2). Na osnovu toga, cilj ovog istraživanja obuhvatio je definisanje uticaja
najznačajnijih faktora hromatografskog sistema na retenciono ponašanje 14 odabranih
liganada imidazolinskih i serotoninskih receptora na mixed-mode stacionarnoj fazi u SFC
uslovima. Uticaj zapreminskog udela metanola (20-30 %), koncentracije amonijum-formijata
(15-25 mM) i temperature (20-30 °C) na vrednosti retencionih faktora (k) odabranih liganada
imidazolinskih i serotoninskih receptora je ispitana primenom centralnog kompozitnog
dizajna (Central Composite Design, CCD) na mixed-mode stacionarnoj fazi. Kao mobilna faza
korišćena je smeša superkritičnog CO2 i metanolnog rastvora amonijum-formijata uz dodatak
0,1% mravlje kiseline. Najznačajniji hromatografski faktori su izdvojeni step-wise postupkom
u višestrukoj linearnoj regresionoj analizi (Multiple Linear Regression, MLR), a njihova
statistička značajnost je procenjena primenom ANOVA testa. U konstruisanim retencionim
modelima, zapremina metanola i koncentracija pufera su pokazale najveći uticaj na retenciono
ponašanje testiranih jedinjenja (r > 0,90; p < 0,05), Slika 1. U koliko se teorijski predviđene
logk vrednosti uporede sa eksperimentalno dobijenim vrednostima na 35% i 15%
zapreminskim udelima metanola u mobilnoj fazi, uočava se da je prisutan visok stepen
slaganja (r > 0,98). Dobijeni rezultati potvrđuju uspešnu primenljivost metodologije
eksperimentalnog dizajna u cilju izvođenja minimalnog broja eksperimenata, prilikom
modelovanja i predikcije retencionog ponašanja liganda imidazolinskih i serotoninskih
receptora u SFC sistemima.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Modeling retention behaviour of imidazoline and serotonin receptor ligands under conditions of green SFC techique, Modelovanje retencionog ponašanja liganada imidazolinskih i serotoninskih receptora u uslovima ekološki bezbedne SFC tehnike",
volume = "71",
number = "5 suplement",
pages = "S126-S129",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4681"
}
Obradović, D., Nikolaevich Stavrianidi, A., Alekseevich Shpigun, O.,& Agbaba, D.. (2021). Modeling retention behaviour of imidazoline and serotonin receptor ligands under conditions of green SFC techique. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 71(5 suplement), S126-S129.
https://hdl.handle.net/21.15107/rcub_farfar_4681
Obradović D, Nikolaevich Stavrianidi A, Alekseevich Shpigun O, Agbaba D. Modeling retention behaviour of imidazoline and serotonin receptor ligands under conditions of green SFC techique. in Arhiv za farmaciju. 2021;71(5 suplement):S126-S129.
https://hdl.handle.net/21.15107/rcub_farfar_4681 .
Obradović, Darija, Nikolaevich Stavrianidi, Andrey, Alekseevich Shpigun, Oleg, Agbaba, Danica, "Modeling retention behaviour of imidazoline and serotonin receptor ligands under conditions of green SFC techique" in Arhiv za farmaciju, 71, no. 5 suplement (2021):S126-S129,
https://hdl.handle.net/21.15107/rcub_farfar_4681 .

Chemometrically Assisted RP-HPLC Method Development for Efficient Separation of Ivabradine and its Eleven Impurities

Tomić, Jovana; Ivković, Branka; Oljačić, Slavica; Nikolić, Katarina; Maljurić, Nevena; Protić, Ana; Agbaba, Danica

(Akademiai Kiado Zrt., 2020)

TY  - JOUR
AU  - Tomić, Jovana
AU  - Ivković, Branka
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
AU  - Maljurić, Nevena
AU  - Protić, Ana
AU  - Agbaba, Danica
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4903
AB  - The aim of this study was to develop a novel reversed-phase high-performance liquid chromatography (RP-HPLC)
method for efficient separation of ivabradine and its 11 impurities. Similar polarity of impurities in the sample mixture
made method optimization challenging and accomplishable only when different chemometric tools, such as
principal component analysis (PCA), Box–Behnken design (BBD), and desirability function as a multicriteria approach,
were employed. The presence of 3 positional isomers (impurities III, V, and VI), keto–enol tautomerism of
impurity VII, and diastereoisomers of impurity X made separation of this complex mixture even more challenging.
Chromatographic retention parameters obtained with the mobile phase consisting of 30 mM phosphate buffer and
acetonitrile (80:20, v/v) on four different RP-HPLC columns at varying pH values (3.0, 4.0, and 5.0) were subjected
to the PCA analysis to select the column with the most appropriate selectivity. Then the column temperature,
pH of the aqueous component of mobile phase, phosphate buffer molarity and the organic solvent content in the
mobile phase were estimated employing BBD. Valid and reliable mathematical models towards resolution of twelve
critical peak pairs were obtained. After determination of the desirability making criteria for all responses, desirability
functions were established and used in optimization. The proposed optimal chromatographic conditions included
the Zorbax Eclipse Plus C18 chromatographic column (100 × 4.6 mm, 3.5 μm), the column temperature of 34 °C,
the mobile phase flow rate of 1.6 mL min−1 and the UV detection at 220 nm. The mobile phase consisted of the
28 mM phosphate buffer at pH 6.0 and acetonitrile (85:15, v/v). Separation of one pair of positional isomers was
not achieved, so methanol was added to the organic part of mobile phase in small increments with the optimal ratio
of methanol to acetonitrile 59:41, v/v. The overall organic component of the mobile phase also increased to 18%,
accelerating the chromatographic analysis.
PB  - Akademiai Kiado Zrt.
T2  - Acta Chromatographica
T1  - Chemometrically Assisted RP-HPLC Method Development for Efficient Separation of Ivabradine and its Eleven Impurities
VL  - 32
IS  - 1
SP  - 53
EP  - 63
DO  - 10.1556/1326.2019.00659
ER  - 
@article{
author = "Tomić, Jovana and Ivković, Branka and Oljačić, Slavica and Nikolić, Katarina and Maljurić, Nevena and Protić, Ana and Agbaba, Danica",
year = "2020",
abstract = "The aim of this study was to develop a novel reversed-phase high-performance liquid chromatography (RP-HPLC)
method for efficient separation of ivabradine and its 11 impurities. Similar polarity of impurities in the sample mixture
made method optimization challenging and accomplishable only when different chemometric tools, such as
principal component analysis (PCA), Box–Behnken design (BBD), and desirability function as a multicriteria approach,
were employed. The presence of 3 positional isomers (impurities III, V, and VI), keto–enol tautomerism of
impurity VII, and diastereoisomers of impurity X made separation of this complex mixture even more challenging.
Chromatographic retention parameters obtained with the mobile phase consisting of 30 mM phosphate buffer and
acetonitrile (80:20, v/v) on four different RP-HPLC columns at varying pH values (3.0, 4.0, and 5.0) were subjected
to the PCA analysis to select the column with the most appropriate selectivity. Then the column temperature,
pH of the aqueous component of mobile phase, phosphate buffer molarity and the organic solvent content in the
mobile phase were estimated employing BBD. Valid and reliable mathematical models towards resolution of twelve
critical peak pairs were obtained. After determination of the desirability making criteria for all responses, desirability
functions were established and used in optimization. The proposed optimal chromatographic conditions included
the Zorbax Eclipse Plus C18 chromatographic column (100 × 4.6 mm, 3.5 μm), the column temperature of 34 °C,
the mobile phase flow rate of 1.6 mL min−1 and the UV detection at 220 nm. The mobile phase consisted of the
28 mM phosphate buffer at pH 6.0 and acetonitrile (85:15, v/v). Separation of one pair of positional isomers was
not achieved, so methanol was added to the organic part of mobile phase in small increments with the optimal ratio
of methanol to acetonitrile 59:41, v/v. The overall organic component of the mobile phase also increased to 18%,
accelerating the chromatographic analysis.",
publisher = "Akademiai Kiado Zrt.",
journal = "Acta Chromatographica",
title = "Chemometrically Assisted RP-HPLC Method Development for Efficient Separation of Ivabradine and its Eleven Impurities",
volume = "32",
number = "1",
pages = "53-63",
doi = "10.1556/1326.2019.00659"
}
Tomić, J., Ivković, B., Oljačić, S., Nikolić, K., Maljurić, N., Protić, A.,& Agbaba, D.. (2020). Chemometrically Assisted RP-HPLC Method Development for Efficient Separation of Ivabradine and its Eleven Impurities. in Acta Chromatographica
Akademiai Kiado Zrt.., 32(1), 53-63.
https://doi.org/10.1556/1326.2019.00659
Tomić J, Ivković B, Oljačić S, Nikolić K, Maljurić N, Protić A, Agbaba D. Chemometrically Assisted RP-HPLC Method Development for Efficient Separation of Ivabradine and its Eleven Impurities. in Acta Chromatographica. 2020;32(1):53-63.
doi:10.1556/1326.2019.00659 .
Tomić, Jovana, Ivković, Branka, Oljačić, Slavica, Nikolić, Katarina, Maljurić, Nevena, Protić, Ana, Agbaba, Danica, "Chemometrically Assisted RP-HPLC Method Development for Efficient Separation of Ivabradine and its Eleven Impurities" in Acta Chromatographica, 32, no. 1 (2020):53-63,
https://doi.org/10.1556/1326.2019.00659 . .
7
1
6

Novel computational approaches to retention modeling in dual hydrophilic interactions/reversed phase chromatography

Obradović, Darija; Komsta, Łukasz; Agbaba, Danica

(Elsevier B.V., 2020)

TY  - JOUR
AU  - Obradović, Darija
AU  - Komsta, Łukasz
AU  - Agbaba, Danica
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3558
AB  - The mixed-mode chromatographic behavior was estimated for imidazoline and serotonin receptor ligands, and their related compounds on dual hydrophilic/reversed phase stationary phase. The Box-Cox transfor- mation was used to obtain the most suitable mathematical equations which describe the mixed-mode retention. Optimal equations were found for the optimization parameter ( λ): λ= -1, λ= -0.5, λ= 0, λ= 0.5, and λ= 1. The proposed equations show satisfactory characteristics compared to standard mul- timodal and quadratic approaches. For a wide range of volume fractions of the mobile phase modifier, crossing between hydrophilic and reversed phase interactions (the turning point) was defined in terms of the minimal retention and the minimum value of the volume fraction of the aqueous eluent in the mobile phase. The cubic spline inter- polation was used as a reference method for estimation of the turning point. It was found out that the newly proposed equations can be used as alternative mathematical forms for the description of the dual retention mechanism and for the evaluation of the turning point. Three new experimental descriptors of the mixed-mode retention were proposed. Two descriptors quan- titatively characterize hydrophilic (log k H ) and reversed phase (log k R ) interactions, while the third one (log k A ) refers to the average retention for the whole HILIC/RP range. It was established that the main fac- tors which control dual nature of the mixed-mode retention are lipophilicity, dipol-dipol, van der Waals and hydrogen bonding interactions. It was concluded that the newly proposed estimations of the retention data reliably characterize the mixed-mode chromatographic behavior.
PB  - Elsevier B.V.
T2  - Journal of Chromatography A
T1  - Novel computational approaches to retention modeling in dual hydrophilic interactions/reversed phase chromatography
VL  - 1619
DO  - 10.1016/j.chroma.2020.460951
ER  - 
@article{
author = "Obradović, Darija and Komsta, Łukasz and Agbaba, Danica",
year = "2020",
abstract = "The mixed-mode chromatographic behavior was estimated for imidazoline and serotonin receptor ligands, and their related compounds on dual hydrophilic/reversed phase stationary phase. The Box-Cox transfor- mation was used to obtain the most suitable mathematical equations which describe the mixed-mode retention. Optimal equations were found for the optimization parameter ( λ): λ= -1, λ= -0.5, λ= 0, λ= 0.5, and λ= 1. The proposed equations show satisfactory characteristics compared to standard mul- timodal and quadratic approaches. For a wide range of volume fractions of the mobile phase modifier, crossing between hydrophilic and reversed phase interactions (the turning point) was defined in terms of the minimal retention and the minimum value of the volume fraction of the aqueous eluent in the mobile phase. The cubic spline inter- polation was used as a reference method for estimation of the turning point. It was found out that the newly proposed equations can be used as alternative mathematical forms for the description of the dual retention mechanism and for the evaluation of the turning point. Three new experimental descriptors of the mixed-mode retention were proposed. Two descriptors quan- titatively characterize hydrophilic (log k H ) and reversed phase (log k R ) interactions, while the third one (log k A ) refers to the average retention for the whole HILIC/RP range. It was established that the main fac- tors which control dual nature of the mixed-mode retention are lipophilicity, dipol-dipol, van der Waals and hydrogen bonding interactions. It was concluded that the newly proposed estimations of the retention data reliably characterize the mixed-mode chromatographic behavior.",
publisher = "Elsevier B.V.",
journal = "Journal of Chromatography A",
title = "Novel computational approaches to retention modeling in dual hydrophilic interactions/reversed phase chromatography",
volume = "1619",
doi = "10.1016/j.chroma.2020.460951"
}
Obradović, D., Komsta, Ł.,& Agbaba, D.. (2020). Novel computational approaches to retention modeling in dual hydrophilic interactions/reversed phase chromatography. in Journal of Chromatography A
Elsevier B.V.., 1619.
https://doi.org/10.1016/j.chroma.2020.460951
Obradović D, Komsta Ł, Agbaba D. Novel computational approaches to retention modeling in dual hydrophilic interactions/reversed phase chromatography. in Journal of Chromatography A. 2020;1619.
doi:10.1016/j.chroma.2020.460951 .
Obradović, Darija, Komsta, Łukasz, Agbaba, Danica, "Novel computational approaches to retention modeling in dual hydrophilic interactions/reversed phase chromatography" in Journal of Chromatography A, 1619 (2020),
https://doi.org/10.1016/j.chroma.2020.460951 . .
12
5
10

Rational design of multi-target compounds with potential anticancer activity

Dobričić, Vladimir; Oluić, Jelena; Nikolić, Katarina; Vučićević, Jelica; Gagić, Žarko; Filipić, Slavica; Agbaba, Danica; Čudina, Olivera

(COST Action 17104 (STRATAGEM), 2019)

TY  - CONF
AU  - Dobričić, Vladimir
AU  - Oluić, Jelena
AU  - Nikolić, Katarina
AU  - Vučićević, Jelica
AU  - Gagić, Žarko
AU  - Filipić, Slavica
AU  - Agbaba, Danica
AU  - Čudina, Olivera
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5473
AB  - Multi-target compounds are designed to act on at least two targets in synergistic way, in order to produce stronger biological effect. The link
between cancer and inflammation has been intensively studied in last years and inhibition of both COX-2 and 5-LOX enzymes may be an
effective therapeutic approach for colon cancer treatment [1]. Acridines are known as DNA-topoisomerase II inhibitors. These compounds
intercalate into the DNA and inhibit topoisomerase II by their side chain. Recent studies showed additional activities of acridine derivatives,
depending on the side chain structure, such as inhibition of Src, MEK and VEGFR2 kinases [2,3]. Altered activity of PI3K/mTOR signaling pathway
is one of the most common aberrations found in various forms of neoplastic lesions. Dual inhibition of PI3K and mTOR represents a reasonably
attractive concept in potential cancer treatment [4]. In this paper, design of three groups of multi-target compounds with potential anticancer
activity is presented. Designed compounds are potential inhibitors of COX-2 and 5-LOX, DNA-topoisomerase II complex and kinases (Src, MEK
and VEGFR2), as well as dual inhibitors of mTOR and PI3K. A set of 27 compounds with published inhibitory activity on COX-2 and 5-LOX was
formed and two QSAR models, for both activities, were created in Pentacle program. On the basis of models’ interpretation, nine new
compounds were designed and activity on both targets predicted by developed models. Twenty-three acridine derivatives were designed and
their interactions with DNA-topoisomerase II complex, Src, MEK and VEGFR2 were tested using AutoDock Vina program. Nineteen designed
compounds bind to DNA similarly to inhibitor amsacrine and among them, ten derivatives show key binding interactions with tested kinases and
therefore possess potential to inhibit them. A dataset of eighty-five compounds with dual PI3K/mTOR inhibitory activities was formed,
divided into two groups based on their structural analogy and 3D-QSAR analysis of each group was performed in Pentacle program,
9
resulting in four QSAR models. On the basis of these results, new compounds were designed and further evaluated by use of molecular
docking, virtual screening and ADMET predictions. Finally, seven compounds were chosen as the most promising new dual mTOR/PI3K inhibitors.
PB  - COST Action 17104 (STRATAGEM)
C3  - STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors, first Working-Group Meeting, WG1 - WG4, 30 - 31. January 2019, Turin, Italy
T1  - Rational design of multi-target compounds with potential anticancer activity
SP  - 8
EP  - 9
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5473
ER  - 
@conference{
author = "Dobričić, Vladimir and Oluić, Jelena and Nikolić, Katarina and Vučićević, Jelica and Gagić, Žarko and Filipić, Slavica and Agbaba, Danica and Čudina, Olivera",
year = "2019",
abstract = "Multi-target compounds are designed to act on at least two targets in synergistic way, in order to produce stronger biological effect. The link
between cancer and inflammation has been intensively studied in last years and inhibition of both COX-2 and 5-LOX enzymes may be an
effective therapeutic approach for colon cancer treatment [1]. Acridines are known as DNA-topoisomerase II inhibitors. These compounds
intercalate into the DNA and inhibit topoisomerase II by their side chain. Recent studies showed additional activities of acridine derivatives,
depending on the side chain structure, such as inhibition of Src, MEK and VEGFR2 kinases [2,3]. Altered activity of PI3K/mTOR signaling pathway
is one of the most common aberrations found in various forms of neoplastic lesions. Dual inhibition of PI3K and mTOR represents a reasonably
attractive concept in potential cancer treatment [4]. In this paper, design of three groups of multi-target compounds with potential anticancer
activity is presented. Designed compounds are potential inhibitors of COX-2 and 5-LOX, DNA-topoisomerase II complex and kinases (Src, MEK
and VEGFR2), as well as dual inhibitors of mTOR and PI3K. A set of 27 compounds with published inhibitory activity on COX-2 and 5-LOX was
formed and two QSAR models, for both activities, were created in Pentacle program. On the basis of models’ interpretation, nine new
compounds were designed and activity on both targets predicted by developed models. Twenty-three acridine derivatives were designed and
their interactions with DNA-topoisomerase II complex, Src, MEK and VEGFR2 were tested using AutoDock Vina program. Nineteen designed
compounds bind to DNA similarly to inhibitor amsacrine and among them, ten derivatives show key binding interactions with tested kinases and
therefore possess potential to inhibit them. A dataset of eighty-five compounds with dual PI3K/mTOR inhibitory activities was formed,
divided into two groups based on their structural analogy and 3D-QSAR analysis of each group was performed in Pentacle program,
9
resulting in four QSAR models. On the basis of these results, new compounds were designed and further evaluated by use of molecular
docking, virtual screening and ADMET predictions. Finally, seven compounds were chosen as the most promising new dual mTOR/PI3K inhibitors.",
publisher = "COST Action 17104 (STRATAGEM)",
journal = "STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors, first Working-Group Meeting, WG1 - WG4, 30 - 31. January 2019, Turin, Italy",
title = "Rational design of multi-target compounds with potential anticancer activity",
pages = "8-9",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5473"
}
Dobričić, V., Oluić, J., Nikolić, K., Vučićević, J., Gagić, Ž., Filipić, S., Agbaba, D.,& Čudina, O.. (2019). Rational design of multi-target compounds with potential anticancer activity. in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors, first Working-Group Meeting, WG1 - WG4, 30 - 31. January 2019, Turin, Italy
COST Action 17104 (STRATAGEM)., 8-9.
https://hdl.handle.net/21.15107/rcub_farfar_5473
Dobričić V, Oluić J, Nikolić K, Vučićević J, Gagić Ž, Filipić S, Agbaba D, Čudina O. Rational design of multi-target compounds with potential anticancer activity. in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors, first Working-Group Meeting, WG1 - WG4, 30 - 31. January 2019, Turin, Italy. 2019;:8-9.
https://hdl.handle.net/21.15107/rcub_farfar_5473 .
Dobričić, Vladimir, Oluić, Jelena, Nikolić, Katarina, Vučićević, Jelica, Gagić, Žarko, Filipić, Slavica, Agbaba, Danica, Čudina, Olivera, "Rational design of multi-target compounds with potential anticancer activity" in STRATAGEM CA17104, New Diagnostic and Therapeutic Tools against Multidrug-Resistant Tumors, first Working-Group Meeting, WG1 - WG4, 30 - 31. January 2019, Turin, Italy (2019):8-9,
https://hdl.handle.net/21.15107/rcub_farfar_5473 .

The evaluation of short- and long-term stability studies for brimonidine in aqueous humor by DPV/BDDE method—possible application for direct assay in native samples

Radulović, Valentina; Aleksić, Mara; Kapetanović, Vera; Rajić, K.K; Jovanović, M; Marjanović, I; Stojković, M; Agbaba, Danica

(Springer Verlag, 2019)

TY  - JOUR
AU  - Radulović, Valentina
AU  - Aleksić, Mara
AU  - Kapetanović, Vera
AU  - Rajić, K.K
AU  - Jovanović, M
AU  - Marjanović, I
AU  - Stojković, M
AU  - Agbaba, Danica
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3286
AB  - A novel voltammetric method was developed for brimonidine (BRIM) determination in deproteinized aqueous humor, simplifying preparation of biological samples for analysis for stability studies. The differential pulse voltammetric (DPV) method using boron doped diamond electrode (BDDE), based on characteristic oxidation peaks, was proposed and successfully applied. The linearity range was within 5.0 × 10−6 to 5.0 × 10−5 M of brimonidine, and limit of detection and limit of quantitation were 1.94 × 10−6 M and 6.46 × 10−6 M, respectively. Intra-day and inter-day precision and accuracy were evaluated and all results were in accordance with validation ICH guidelines. The best short-term stability study results were obtained for a concentration level of 3.0 × 10−5 M expressed by deviation of + 1.86% between initial and post storage concentrations. A long-term stability study was performed for two concentrations of 3.0 × 10−5 M and 5.0 × 10−5 M and resulted in deviations of + 1.63% and + 3.56%, respectively. A freeze and thaw stability study indicated that samples might be frozen only once. The enhancement of DPV/BDDE method sensitivity gained by modification, for the analysis of immeasurable BRIM quantities in native, untreated aqueous humor, was reached for quantities of 6 or 12 nmol/0.1 mL aqueous humor with acceptable accuracy (up to + 7.5%). The nature of the process—the irreversible one electron oxidation voltammetric peak of BRIM—limited the sensitivity. Only electrochemical pre-treatment of the BDD electrode before each measurement significantly speeded up the whole procedure. The advantages of the proposed method are simplicity, short-time performance, and good specificity/selectivity, as well as satisfactory accuracy, and no chemical modification of BDDE was necessary.
PB  - Springer Verlag
T2  - Analytical and Bioanalytical Chemistry
T1  - The evaluation of short- and long-term stability studies for brimonidine in aqueous humor by DPV/BDDE method—possible application for direct assay in native samples
DO  - 10.1007/s00216-019-01955-3
ER  - 
@article{
author = "Radulović, Valentina and Aleksić, Mara and Kapetanović, Vera and Rajić, K.K and Jovanović, M and Marjanović, I and Stojković, M and Agbaba, Danica",
year = "2019",
abstract = "A novel voltammetric method was developed for brimonidine (BRIM) determination in deproteinized aqueous humor, simplifying preparation of biological samples for analysis for stability studies. The differential pulse voltammetric (DPV) method using boron doped diamond electrode (BDDE), based on characteristic oxidation peaks, was proposed and successfully applied. The linearity range was within 5.0 × 10−6 to 5.0 × 10−5 M of brimonidine, and limit of detection and limit of quantitation were 1.94 × 10−6 M and 6.46 × 10−6 M, respectively. Intra-day and inter-day precision and accuracy were evaluated and all results were in accordance with validation ICH guidelines. The best short-term stability study results were obtained for a concentration level of 3.0 × 10−5 M expressed by deviation of + 1.86% between initial and post storage concentrations. A long-term stability study was performed for two concentrations of 3.0 × 10−5 M and 5.0 × 10−5 M and resulted in deviations of + 1.63% and + 3.56%, respectively. A freeze and thaw stability study indicated that samples might be frozen only once. The enhancement of DPV/BDDE method sensitivity gained by modification, for the analysis of immeasurable BRIM quantities in native, untreated aqueous humor, was reached for quantities of 6 or 12 nmol/0.1 mL aqueous humor with acceptable accuracy (up to + 7.5%). The nature of the process—the irreversible one electron oxidation voltammetric peak of BRIM—limited the sensitivity. Only electrochemical pre-treatment of the BDD electrode before each measurement significantly speeded up the whole procedure. The advantages of the proposed method are simplicity, short-time performance, and good specificity/selectivity, as well as satisfactory accuracy, and no chemical modification of BDDE was necessary.",
publisher = "Springer Verlag",
journal = "Analytical and Bioanalytical Chemistry",
title = "The evaluation of short- and long-term stability studies for brimonidine in aqueous humor by DPV/BDDE method—possible application for direct assay in native samples",
doi = "10.1007/s00216-019-01955-3"
}
Radulović, V., Aleksić, M., Kapetanović, V., Rajić, K.K, Jovanović, M., Marjanović, I., Stojković, M.,& Agbaba, D.. (2019). The evaluation of short- and long-term stability studies for brimonidine in aqueous humor by DPV/BDDE method—possible application for direct assay in native samples. in Analytical and Bioanalytical Chemistry
Springer Verlag..
https://doi.org/10.1007/s00216-019-01955-3
Radulović V, Aleksić M, Kapetanović V, Rajić K, Jovanović M, Marjanović I, Stojković M, Agbaba D. The evaluation of short- and long-term stability studies for brimonidine in aqueous humor by DPV/BDDE method—possible application for direct assay in native samples. in Analytical and Bioanalytical Chemistry. 2019;.
doi:10.1007/s00216-019-01955-3 .
Radulović, Valentina, Aleksić, Mara, Kapetanović, Vera, Rajić, K.K, Jovanović, M, Marjanović, I, Stojković, M, Agbaba, Danica, "The evaluation of short- and long-term stability studies for brimonidine in aqueous humor by DPV/BDDE method—possible application for direct assay in native samples" in Analytical and Bioanalytical Chemistry (2019),
https://doi.org/10.1007/s00216-019-01955-3 . .
1
1
1

Investigation and prediction of retention characteristics of selected set of central nervous system active compounds on mixed-mode diol stationary phase

Obradović, Darija; Oljačić, Slavica; Nikolić, Katarina; Agbaba, Danica

(Institute of Chemistry University of Silesia in Katowice, 2019)

TY  - CONF
AU  - Obradović, Darija
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5156
AB  - Investigation of the retention behavior of a wide range of analytes (43 nitrogen containing heterocyclic
and guanidine derivatives such, as imidazoline and serotonin receptor ligands, or their related
compounds) was performed on the mixed-mode stationary phase in the combined
reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC) modes. The imidazoline
receptor ligands are the imidazoline or guanidine analogues with numerous therapeutic applications
(such, as antihypertensives, diuretics, antiallergenics, antidiabetics, and antipsychotics), while the
serotonin receptor ligands are the piperazine derivatives which exert an effect on positive and negative
symptoms of schizophrenia, mania and mixed states of bipolar disorder.
On the mixed-mode stationary phase, the retention behaviour of investigated compounds
was described as a function of the aqueous eluent volume fractions, φ(aq), and total polarity of mobile
phase (Ptot). The turning point was discussed based on different mobile phase characteristics
representing the shift between the HILIC and the RP chromatographic mode. The influence
of molecular properties on the main retention characteristics (turining point and the extrapolated
retention parameters) is going to be discussed.
PB  - Institute of Chemistry University of Silesia in Katowice
C3  - 42nd Symposium Chromatographic Methods of Investigating Organic Compounds, Book of Abstracts
T1  - Investigation and prediction of retention characteristics of selected set of central nervous system active compounds on mixed-mode diol stationary phase
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5156
ER  - 
@conference{
author = "Obradović, Darija and Oljačić, Slavica and Nikolić, Katarina and Agbaba, Danica",
year = "2019",
abstract = "Investigation of the retention behavior of a wide range of analytes (43 nitrogen containing heterocyclic
and guanidine derivatives such, as imidazoline and serotonin receptor ligands, or their related
compounds) was performed on the mixed-mode stationary phase in the combined
reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC) modes. The imidazoline
receptor ligands are the imidazoline or guanidine analogues with numerous therapeutic applications
(such, as antihypertensives, diuretics, antiallergenics, antidiabetics, and antipsychotics), while the
serotonin receptor ligands are the piperazine derivatives which exert an effect on positive and negative
symptoms of schizophrenia, mania and mixed states of bipolar disorder.
On the mixed-mode stationary phase, the retention behaviour of investigated compounds
was described as a function of the aqueous eluent volume fractions, φ(aq), and total polarity of mobile
phase (Ptot). The turning point was discussed based on different mobile phase characteristics
representing the shift between the HILIC and the RP chromatographic mode. The influence
of molecular properties on the main retention characteristics (turining point and the extrapolated
retention parameters) is going to be discussed.",
publisher = "Institute of Chemistry University of Silesia in Katowice",
journal = "42nd Symposium Chromatographic Methods of Investigating Organic Compounds, Book of Abstracts",
title = "Investigation and prediction of retention characteristics of selected set of central nervous system active compounds on mixed-mode diol stationary phase",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5156"
}
Obradović, D., Oljačić, S., Nikolić, K.,& Agbaba, D.. (2019). Investigation and prediction of retention characteristics of selected set of central nervous system active compounds on mixed-mode diol stationary phase. in 42nd Symposium Chromatographic Methods of Investigating Organic Compounds, Book of Abstracts
Institute of Chemistry University of Silesia in Katowice..
https://hdl.handle.net/21.15107/rcub_farfar_5156
Obradović D, Oljačić S, Nikolić K, Agbaba D. Investigation and prediction of retention characteristics of selected set of central nervous system active compounds on mixed-mode diol stationary phase. in 42nd Symposium Chromatographic Methods of Investigating Organic Compounds, Book of Abstracts. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_5156 .
Obradović, Darija, Oljačić, Slavica, Nikolić, Katarina, Agbaba, Danica, "Investigation and prediction of retention characteristics of selected set of central nervous system active compounds on mixed-mode diol stationary phase" in 42nd Symposium Chromatographic Methods of Investigating Organic Compounds, Book of Abstracts (2019),
https://hdl.handle.net/21.15107/rcub_farfar_5156 .

Analysis of the retention behavior of selected antiarrhythmics by means of thin-layer chromatography

Obradović, Darija; Jovanović, Dušan; Pesić, Suncica; Tomić, Jovana; Oljačić, Slavica; Nikolić, Katarina; Agbaba, Danica

(Taylor & Francis Inc, Philadelphia, 2019)

TY  - JOUR
AU  - Obradović, Darija
AU  - Jovanović, Dušan
AU  - Pesić, Suncica
AU  - Tomić, Jovana
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3368
AB  - The retention behavior of ivabradine, its 11 related compounds, diltiazem and verapamil has been examined by thin-layer chromatography using non-polar stationary phase (RP-18) and the following mobile phases: methanol-6.25% aqueous ammonia, tetrahydrofuran - 6.25% aqueous ammonia, and also polar stationary phase (silica gel) with tetrahydrofuran - 6.25% methanolic ammonia as mobile phase. In the examined chromatographic systems, linear relationships were established between the retention coefficients, R-M(0) and m, and molecular properties of the investigated antiarrhythmic drugs. The Quantitative Structure Retention Relationship (QSRR) modeling was performed with use of the stepwise multiple linear regression, in order to select the most important molecular properties which influence the retention behavior. The developed models revealed that apart from lipophilicity also the molecular volume (V), and the hydrogen bond basicity (B) of the tested compounds are the most important for the retention behavior in the examined chromatographic systems.
PB  - Taylor & Francis Inc, Philadelphia
T2  - Journal of Liquid Chromatography & Related Technologies
T1  - Analysis of the retention behavior of selected antiarrhythmics by means of thin-layer chromatography
SP  - 1
EP  - 7
DO  - 10.1080/10826076.2019.1585613
ER  - 
@article{
author = "Obradović, Darija and Jovanović, Dušan and Pesić, Suncica and Tomić, Jovana and Oljačić, Slavica and Nikolić, Katarina and Agbaba, Danica",
year = "2019",
abstract = "The retention behavior of ivabradine, its 11 related compounds, diltiazem and verapamil has been examined by thin-layer chromatography using non-polar stationary phase (RP-18) and the following mobile phases: methanol-6.25% aqueous ammonia, tetrahydrofuran - 6.25% aqueous ammonia, and also polar stationary phase (silica gel) with tetrahydrofuran - 6.25% methanolic ammonia as mobile phase. In the examined chromatographic systems, linear relationships were established between the retention coefficients, R-M(0) and m, and molecular properties of the investigated antiarrhythmic drugs. The Quantitative Structure Retention Relationship (QSRR) modeling was performed with use of the stepwise multiple linear regression, in order to select the most important molecular properties which influence the retention behavior. The developed models revealed that apart from lipophilicity also the molecular volume (V), and the hydrogen bond basicity (B) of the tested compounds are the most important for the retention behavior in the examined chromatographic systems.",
publisher = "Taylor & Francis Inc, Philadelphia",
journal = "Journal of Liquid Chromatography & Related Technologies",
title = "Analysis of the retention behavior of selected antiarrhythmics by means of thin-layer chromatography",
pages = "1-7",
doi = "10.1080/10826076.2019.1585613"
}
Obradović, D., Jovanović, D., Pesić, S., Tomić, J., Oljačić, S., Nikolić, K.,& Agbaba, D.. (2019). Analysis of the retention behavior of selected antiarrhythmics by means of thin-layer chromatography. in Journal of Liquid Chromatography & Related Technologies
Taylor & Francis Inc, Philadelphia., 1-7.
https://doi.org/10.1080/10826076.2019.1585613
Obradović D, Jovanović D, Pesić S, Tomić J, Oljačić S, Nikolić K, Agbaba D. Analysis of the retention behavior of selected antiarrhythmics by means of thin-layer chromatography. in Journal of Liquid Chromatography & Related Technologies. 2019;:1-7.
doi:10.1080/10826076.2019.1585613 .
Obradović, Darija, Jovanović, Dušan, Pesić, Suncica, Tomić, Jovana, Oljačić, Slavica, Nikolić, Katarina, Agbaba, Danica, "Analysis of the retention behavior of selected antiarrhythmics by means of thin-layer chromatography" in Journal of Liquid Chromatography & Related Technologies (2019):1-7,
https://doi.org/10.1080/10826076.2019.1585613 . .
1
7
1

Investigation and prediction of retention characteristics of imidazoline and serotonin receptor ligands and their related compounds on mixed-mode stationary phase

Obradović, Darija; Oljačić, Slavica; Nikolić, Katarina; Agbaba, Danica

(Elsevier Science BV, Amsterdam, 2019)

TY  - JOUR
AU  - Obradović, Darija
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3332
AB  - Investigation of the retention behavior of a wide range of analytes, 43 nitrogen containing heterocyclic and guanidine derivatives such, as imidazoline and serotonin receptor ligands or their related compounds. was performed on mixed-mode stationary phase in the combined reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC) modes. Suitability of the linear retention modelling in the HILIC and RP modes was tested including separate contributions from adsorption and partition. For the HILIC retention, the partition model was found to provide better description compared with the adsorption model. In a wider range of the aqueous eluent volume fractions, phi(aq), retention was described as a function of volume fractions and total polarity of mobile phase using the mixed-mode retention modelling. The obtained results revealed that the shift of the chromatographic mode can be calculated from the change of total polarity of mobile phase in a multimodal relation, logarithm of retention factor vs. total polarity, with the minimum value representing the turning point between the HILIC and the RP mode. Molecular properties of the investigated compounds that influence the retention behavior and the turning point were selected using Multiple Linear Regression (MLR) and Support Vector Machine (SVM). Slightly better statistical results were found for the logk(w)(RP)(aq)/MLR, logk(w)(HILIC) (org)/MLR, logk(b)(HILIC)(aq)/MLR, and phi(min) (aq)/SVM (RBF) QSRR models than for the logk(w)(RP)(aq)/SVM, logk(w)(NILIC)(org)/SVM, logk(b)(HILIC)(aq)/SVM. and phi(min)(aq)/MLR modelling. With this insight, it is possible to precisely define and predict the retention characteristics based on physicochemical properties of imidazoline and piperazine related compounds.
PB  - Elsevier Science BV, Amsterdam
T2  - Journal of Chromatography A
T1  - Investigation and prediction of retention characteristics of imidazoline and serotonin receptor ligands and their related compounds on mixed-mode stationary phase
VL  - 1585
SP  - 92
EP  - 104
DO  - 10.1016/j.chroma.2018.11.051
ER  - 
@article{
author = "Obradović, Darija and Oljačić, Slavica and Nikolić, Katarina and Agbaba, Danica",
year = "2019",
abstract = "Investigation of the retention behavior of a wide range of analytes, 43 nitrogen containing heterocyclic and guanidine derivatives such, as imidazoline and serotonin receptor ligands or their related compounds. was performed on mixed-mode stationary phase in the combined reversed-phase (RP) and hydrophilic interaction liquid chromatography (HILIC) modes. Suitability of the linear retention modelling in the HILIC and RP modes was tested including separate contributions from adsorption and partition. For the HILIC retention, the partition model was found to provide better description compared with the adsorption model. In a wider range of the aqueous eluent volume fractions, phi(aq), retention was described as a function of volume fractions and total polarity of mobile phase using the mixed-mode retention modelling. The obtained results revealed that the shift of the chromatographic mode can be calculated from the change of total polarity of mobile phase in a multimodal relation, logarithm of retention factor vs. total polarity, with the minimum value representing the turning point between the HILIC and the RP mode. Molecular properties of the investigated compounds that influence the retention behavior and the turning point were selected using Multiple Linear Regression (MLR) and Support Vector Machine (SVM). Slightly better statistical results were found for the logk(w)(RP)(aq)/MLR, logk(w)(HILIC) (org)/MLR, logk(b)(HILIC)(aq)/MLR, and phi(min) (aq)/SVM (RBF) QSRR models than for the logk(w)(RP)(aq)/SVM, logk(w)(NILIC)(org)/SVM, logk(b)(HILIC)(aq)/SVM. and phi(min)(aq)/MLR modelling. With this insight, it is possible to precisely define and predict the retention characteristics based on physicochemical properties of imidazoline and piperazine related compounds.",
publisher = "Elsevier Science BV, Amsterdam",
journal = "Journal of Chromatography A",
title = "Investigation and prediction of retention characteristics of imidazoline and serotonin receptor ligands and their related compounds on mixed-mode stationary phase",
volume = "1585",
pages = "92-104",
doi = "10.1016/j.chroma.2018.11.051"
}
Obradović, D., Oljačić, S., Nikolić, K.,& Agbaba, D.. (2019). Investigation and prediction of retention characteristics of imidazoline and serotonin receptor ligands and their related compounds on mixed-mode stationary phase. in Journal of Chromatography A
Elsevier Science BV, Amsterdam., 1585, 92-104.
https://doi.org/10.1016/j.chroma.2018.11.051
Obradović D, Oljačić S, Nikolić K, Agbaba D. Investigation and prediction of retention characteristics of imidazoline and serotonin receptor ligands and their related compounds on mixed-mode stationary phase. in Journal of Chromatography A. 2019;1585:92-104.
doi:10.1016/j.chroma.2018.11.051 .
Obradović, Darija, Oljačić, Slavica, Nikolić, Katarina, Agbaba, Danica, "Investigation and prediction of retention characteristics of imidazoline and serotonin receptor ligands and their related compounds on mixed-mode stationary phase" in Journal of Chromatography A, 1585 (2019):92-104,
https://doi.org/10.1016/j.chroma.2018.11.051 . .
14
7
12

Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors

Ružić, Dušan; Đoković, Nemanja; Petković, Miloš; Agbaba, Danica; Gul, Sheraz; Lahtela-Kakkonen, Maija; Ganesan, A.; Nikolić, Katarina

(EuChemS (European Chemical Society), 2019)

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Gul, Sheraz
AU  - Lahtela-Kakkonen, Maija
AU  - Ganesan, A.
AU  - Nikolić, Katarina
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4946
PB  - EuChemS (European Chemical Society)
C3  - 12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts
T1  - Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4946
ER  - 
@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Gul, Sheraz and Lahtela-Kakkonen, Maija and Ganesan, A. and Nikolić, Katarina",
year = "2019",
publisher = "EuChemS (European Chemical Society)",
journal = "12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts",
title = "Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4946"
}
Ružić, D., Đoković, N., Petković, M., Agbaba, D., Gul, S., Lahtela-Kakkonen, M., Ganesan, A.,& Nikolić, K.. (2019). Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors. in 12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts
EuChemS (European Chemical Society)..
https://hdl.handle.net/21.15107/rcub_farfar_4946
Ružić D, Đoković N, Petković M, Agbaba D, Gul S, Lahtela-Kakkonen M, Ganesan A, Nikolić K. Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors. in 12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_4946 .
Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Gul, Sheraz, Lahtela-Kakkonen, Maija, Ganesan, A., Nikolić, Katarina, "Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors" in 12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts (2019),
https://hdl.handle.net/21.15107/rcub_farfar_4946 .

Rational design and evaluation of selective HDAC inhibitors

Ružić, Dušan; Đoković, Nemanja; Petković, Miloš; Agbaba, Danica; Gul, Sheraz; Lahtela-Kakkonen, Maija; Ganesan, A.; Nikolić, Katarina

(European Cooperation in Science and Technology (COST), 2019)

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Gul, Sheraz
AU  - Lahtela-Kakkonen, Maija
AU  - Ganesan, A.
AU  - Nikolić, Katarina
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4945
PB  - European Cooperation in Science and Technology (COST)
C3  - COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019.
T1  - Rational design and evaluation of selective HDAC inhibitors
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4945
ER  - 
@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Gul, Sheraz and Lahtela-Kakkonen, Maija and Ganesan, A. and Nikolić, Katarina",
year = "2019",
publisher = "European Cooperation in Science and Technology (COST)",
journal = "COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019.",
title = "Rational design and evaluation of selective HDAC inhibitors",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4945"
}
Ružić, D., Đoković, N., Petković, M., Agbaba, D., Gul, S., Lahtela-Kakkonen, M., Ganesan, A.,& Nikolić, K.. (2019). Rational design and evaluation of selective HDAC inhibitors. in COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019.
European Cooperation in Science and Technology (COST)..
https://hdl.handle.net/21.15107/rcub_farfar_4945
Ružić D, Đoković N, Petković M, Agbaba D, Gul S, Lahtela-Kakkonen M, Ganesan A, Nikolić K. Rational design and evaluation of selective HDAC inhibitors. in COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019.. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_4945 .
Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Gul, Sheraz, Lahtela-Kakkonen, Maija, Ganesan, A., Nikolić, Katarina, "Rational design and evaluation of selective HDAC inhibitors" in COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019. (2019),
https://hdl.handle.net/21.15107/rcub_farfar_4945 .

Identification of potential dual histamine H3 receptor antagonist and serotonin reuptake inhibitors through ligand-based and structure-based approaches

Đoković, Nemanja; Nikolić, Katarina; Agbaba, Danica

(Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu, 2019)

TY  - CONF
AU  - Đoković, Nemanja
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4888
AB  - The major depressive disorder (MDD), routinely treated with selective serotonin reuptake inhibitors (SSRIs), is the second
leading cause of disability worldwide. However, the treatment of MDD is complicated by high prevalence of residual symptoms
connected to increased risk of relapse. Some of the most common residual symptoms are cognitive dysfunction and fatigue.
Histamine H3 receptor (H3R) antagonists are both, pro-cognitive and wake-promoting agents. In pre-clinical study it was
suggested that dual histamine H3R antagonist and SSRI may have utility as a more efficient antidepressant therapy. The aim of
this in silico study was identification of novel dual SSRI/H3R antagonist using ligand-based and structure-based drug design
techniques. Starting from structures and activities of known dual ligands, two GRIND-based 3D-QSAR models have been
developed, SERT model (R2 = 0.97; Q2 = 0.79; SDEP= 0.124) and H3R model (R2 = 0.86; Q2 = 0.75; SDEP= 0.184), and 3Dpharmacophores
were constructed. Further, homology model of H3R was built and refined with molecular dynamics. The
hypotheses of binding modes for dual ligands were generated with molecular docking on H3R model and X-ray structure of
SERT. In the second part of this study, ligand-based and structure-based virtual screening models were generated and
validated. Prospective screening of ZINC database was performed in order to extract novel chemotypes of dual ligands. Final
selection of ligands was performed based on generated pharmacophore and docking models as well as predicted
pharmacokinetic properties. Few novel compounds were emphasized as promising starting point for development of new
classes of dual antidepressants.
PB  - Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu
C3  - 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, Farmaceutski fakultet, Univerzitet u Beogradu, 9. maj 2019.
T1  - Identification of potential dual histamine H3 receptor antagonist and serotonin reuptake inhibitors through ligand-based and structure-based approaches
SP  - 14
EP  - 14
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4888
ER  - 
@conference{
author = "Đoković, Nemanja and Nikolić, Katarina and Agbaba, Danica",
year = "2019",
abstract = "The major depressive disorder (MDD), routinely treated with selective serotonin reuptake inhibitors (SSRIs), is the second
leading cause of disability worldwide. However, the treatment of MDD is complicated by high prevalence of residual symptoms
connected to increased risk of relapse. Some of the most common residual symptoms are cognitive dysfunction and fatigue.
Histamine H3 receptor (H3R) antagonists are both, pro-cognitive and wake-promoting agents. In pre-clinical study it was
suggested that dual histamine H3R antagonist and SSRI may have utility as a more efficient antidepressant therapy. The aim of
this in silico study was identification of novel dual SSRI/H3R antagonist using ligand-based and structure-based drug design
techniques. Starting from structures and activities of known dual ligands, two GRIND-based 3D-QSAR models have been
developed, SERT model (R2 = 0.97; Q2 = 0.79; SDEP= 0.124) and H3R model (R2 = 0.86; Q2 = 0.75; SDEP= 0.184), and 3Dpharmacophores
were constructed. Further, homology model of H3R was built and refined with molecular dynamics. The
hypotheses of binding modes for dual ligands were generated with molecular docking on H3R model and X-ray structure of
SERT. In the second part of this study, ligand-based and structure-based virtual screening models were generated and
validated. Prospective screening of ZINC database was performed in order to extract novel chemotypes of dual ligands. Final
selection of ligands was performed based on generated pharmacophore and docking models as well as predicted
pharmacokinetic properties. Few novel compounds were emphasized as promising starting point for development of new
classes of dual antidepressants.",
publisher = "Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu",
journal = "2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, Farmaceutski fakultet, Univerzitet u Beogradu, 9. maj 2019.",
title = "Identification of potential dual histamine H3 receptor antagonist and serotonin reuptake inhibitors through ligand-based and structure-based approaches",
pages = "14-14",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4888"
}
Đoković, N., Nikolić, K.,& Agbaba, D.. (2019). Identification of potential dual histamine H3 receptor antagonist and serotonin reuptake inhibitors through ligand-based and structure-based approaches. in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, Farmaceutski fakultet, Univerzitet u Beogradu, 9. maj 2019.
Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu., 14-14.
https://hdl.handle.net/21.15107/rcub_farfar_4888
Đoković N, Nikolić K, Agbaba D. Identification of potential dual histamine H3 receptor antagonist and serotonin reuptake inhibitors through ligand-based and structure-based approaches. in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, Farmaceutski fakultet, Univerzitet u Beogradu, 9. maj 2019.. 2019;:14-14.
https://hdl.handle.net/21.15107/rcub_farfar_4888 .
Đoković, Nemanja, Nikolić, Katarina, Agbaba, Danica, "Identification of potential dual histamine H3 receptor antagonist and serotonin reuptake inhibitors through ligand-based and structure-based approaches" in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, Farmaceutski fakultet, Univerzitet u Beogradu, 9. maj 2019. (2019):14-14,
https://hdl.handle.net/21.15107/rcub_farfar_4888 .

Structure and ligand based drug design strategies in the development of novel serotonin 5-HTt2a receptor antagonists

Radan, Milica; Antonijević, Mirjana; Ružić, Dušan; Đikić, Teodora; Agbaba, Danica; Nikolić, Katarina

(Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu, 2019)

TY  - CONF
AU  - Radan, Milica
AU  - Antonijević, Mirjana
AU  - Ružić, Dušan
AU  - Đikić, Teodora
AU  - Agbaba, Danica
AU  - Nikolić, Katarina
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4886
AB  - The serotonin 5-HT2A receptors are widely distributed throughout the central and the peripheral nervous system where they
play a key role in many physiological functions. Abnormal activity of 5-HT2A receptors is associated with various neurological
disorders, such as depression, schizophrenia, anxiety, and Parkinson disease. In order to analyze 3D-structure of the pharmacophore as well as binding kinetics of 5-HT2A-R antagonists, we have combined ligand and structure based approaches.
Three-dimensional quantitative structure-activity relationship (3D-QSAR) study in combination with molecular docking and
molecular dynamic (MD) simulation was used to identify key substituents responsible for high binding affinity and selectivity of
5-HT2A antagonists. The study was performed on wide range of structurally diverse antagonists that were divided into three
different clusters: clozapine, ziprasidone, and CHEMBL240876 derivates. We have obtained three different inactive, antagonistbound,
conformations of this receptor by using the 50ns long MD simulations with each cluster representative. Subsequently,
these conformations were used as templates for docking studies in order to find virtually bioactive conformations of ligands.
Selected virtually bioactive conformations were used for calculation of specific molecular descriptors (Grid Independent
Descriptors- GRIND) and 3D-QSAR model building. The 3D-QSAR approach was used to select the most influential variables
which were used for clarifying the structural features required for 5-HT2A antagonists. The reliability and predictive power of the
model was assessed using an external test set compounds and showed reasonable external predictability. The study provides
valuable information about the key structural features that are required in the rational drug design of novel 5-HT2A antagonists.
PB  - Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu
C3  - 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019.
T1  - Structure and ligand based drug design strategies in the development of novel serotonin 5-HTt2a receptor antagonists
SP  - 14
EP  - 15
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4886
ER  - 
@conference{
author = "Radan, Milica and Antonijević, Mirjana and Ružić, Dušan and Đikić, Teodora and Agbaba, Danica and Nikolić, Katarina",
year = "2019",
abstract = "The serotonin 5-HT2A receptors are widely distributed throughout the central and the peripheral nervous system where they
play a key role in many physiological functions. Abnormal activity of 5-HT2A receptors is associated with various neurological
disorders, such as depression, schizophrenia, anxiety, and Parkinson disease. In order to analyze 3D-structure of the pharmacophore as well as binding kinetics of 5-HT2A-R antagonists, we have combined ligand and structure based approaches.
Three-dimensional quantitative structure-activity relationship (3D-QSAR) study in combination with molecular docking and
molecular dynamic (MD) simulation was used to identify key substituents responsible for high binding affinity and selectivity of
5-HT2A antagonists. The study was performed on wide range of structurally diverse antagonists that were divided into three
different clusters: clozapine, ziprasidone, and CHEMBL240876 derivates. We have obtained three different inactive, antagonistbound,
conformations of this receptor by using the 50ns long MD simulations with each cluster representative. Subsequently,
these conformations were used as templates for docking studies in order to find virtually bioactive conformations of ligands.
Selected virtually bioactive conformations were used for calculation of specific molecular descriptors (Grid Independent
Descriptors- GRIND) and 3D-QSAR model building. The 3D-QSAR approach was used to select the most influential variables
which were used for clarifying the structural features required for 5-HT2A antagonists. The reliability and predictive power of the
model was assessed using an external test set compounds and showed reasonable external predictability. The study provides
valuable information about the key structural features that are required in the rational drug design of novel 5-HT2A antagonists.",
publisher = "Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu",
journal = "2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019.",
title = "Structure and ligand based drug design strategies in the development of novel serotonin 5-HTt2a receptor antagonists",
pages = "14-15",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4886"
}
Radan, M., Antonijević, M., Ružić, D., Đikić, T., Agbaba, D.,& Nikolić, K.. (2019). Structure and ligand based drug design strategies in the development of novel serotonin 5-HTt2a receptor antagonists. in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019.
Centar za eksperimentalnu i primenjenu fiziologiju Farmaceutskog fakulteta Univerziteta u Beogradu., 14-15.
https://hdl.handle.net/21.15107/rcub_farfar_4886
Radan M, Antonijević M, Ružić D, Đikić T, Agbaba D, Nikolić K. Structure and ligand based drug design strategies in the development of novel serotonin 5-HTt2a receptor antagonists. in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019.. 2019;:14-15.
https://hdl.handle.net/21.15107/rcub_farfar_4886 .
Radan, Milica, Antonijević, Mirjana, Ružić, Dušan, Đikić, Teodora, Agbaba, Danica, Nikolić, Katarina, "Structure and ligand based drug design strategies in the development of novel serotonin 5-HTt2a receptor antagonists" in 2. Simpozijum iz biomedicine: bazična i klinička Neuronauka, KNJIGA SAŽETAKA, Farmaceutski fakultet - Univerzitet u Beogradu, 9. maj 2019. (2019):14-15,
https://hdl.handle.net/21.15107/rcub_farfar_4886 .