TY  - CONF
AU  - Nikolić, Katarina
AU  - Radan, Milica
AU  - Đikić, Teodora
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4762
PB  - European Research Network on Signal Transduction CA18133 (ERNEST)
C3  - 8th and final ERNEST Meeting "GPCR structure and function: The present and perspectives for the future”, May 3-7, 2023 in Crete, Greece
T1  - Polypharmacological strategy in rational drug design of new dual 5HT2A/D2-R antagonists as potentially effective therapeutics of complex neurological and mental disorders
SP  - 125
EP  - 125
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4762
ER  - 

@conference{
author = "Nikolić, Katarina and Radan, Milica and Đikić, Teodora",
year = "2023",
publisher = "European Research Network on Signal Transduction CA18133 (ERNEST)",
journal = "8th and final ERNEST Meeting "GPCR structure and function: The present and perspectives for the future”, May 3-7, 2023 in Crete, Greece",
title = "Polypharmacological strategy in rational drug design of new dual 5HT2A/D2-R antagonists as potentially effective therapeutics of complex neurological and mental disorders",
pages = "125-125",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4762"
}

Nikolić, K., Radan, M.,& Đikić, T.. (2023). Polypharmacological strategy in rational drug design of new dual 5HT2A/D2-R antagonists as potentially effective therapeutics of complex neurological and mental disorders. in 8th and final ERNEST Meeting "GPCR structure and function: The present and perspectives for the future”, May 3-7, 2023 in Crete, Greece
European Research Network on Signal Transduction CA18133 (ERNEST)., 125-125.
https://hdl.handle.net/21.15107/rcub_farfar_4762

Nikolić K, Radan M, Đikić T. Polypharmacological strategy in rational drug design of new dual 5HT2A/D2-R antagonists as potentially effective therapeutics of complex neurological and mental disorders. in 8th and final ERNEST Meeting "GPCR structure and function: The present and perspectives for the future”, May 3-7, 2023 in Crete, Greece. 2023;:125-125.
https://hdl.handle.net/21.15107/rcub_farfar_4762 .

Nikolić, Katarina, Radan, Milica, Đikić, Teodora, "Polypharmacological strategy in rational drug design of new dual 5HT2A/D2-R antagonists as potentially effective therapeutics of complex neurological and mental disorders" in 8th and final ERNEST Meeting "GPCR structure and function: The present and perspectives for the future”, May 3-7, 2023 in Crete, Greece (2023):125-125,
https://hdl.handle.net/21.15107/rcub_farfar_4762 .

TY  - JOUR
AU  - Popović‑Nikolić, Marija
AU  - Nikolić, Katarina
AU  - Popović, Gordana
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4687
AB  - The acid–base equilibria of six ACE inhibitors (ACEIs), captopril, cilazapril, enalapril, lisinopril, quinapril, and rami-
pril, were investigated in the presence of micelles of nonionic surfactant Brij 35. The pKa values were potentiometrically
determined at 25 °C and at a constant ionic strength (0.1 M NaCl). The obtained potentiometric data were evaluated in the
computer program Hyperquad. On the basis of the shift in the pKa values (ΔpKa ) determined in micellar media in relation
to the pKa values previously determined in “pure” water, the effect of Brij 35 micelles on ACEIs ionization was estimated.
The presence of nonionic Brij 35 micelles caused a shift in the pKa values of all ionizable groups of the investigated ACEIs
(ΔpKa from − 3.44 to + 1.9) while shifting the protolytic equilibria of both acidic and basic groups toward the molecular
form. The Brij 35 micelles expressed the most pronounced effect on the ionization of captopril among the investigated ACEIs
and stronger effect on the ionization of amino than on the ionization of carboxyl groups. The obtained results suggest that
ionizable functional groups of ACEIs are involved in interactions with palisade layer of nonionic Brij 35 micelles, which
potentially can be considered in physiological conditions. Distribution diagrams of the investigated ACEIs equilibrium
forms as a function of pH indicate that the change in distribution is most strongly expressed in pH range 4–8, which includes
biopharmaceutically important pH values.
PB  - Springer
T2  - Monatshefte für Chemie - Chemical Monthly
T1  - Protolytic equilibria of ACE inhibitors in micellar solution of nonionic surfactant Brij 35
DO  - 10.1007/s00706-023-03059-2
ER  - 

@article{
author = "Popović‑Nikolić, Marija and Nikolić, Katarina and Popović, Gordana",
year = "2023",
abstract = "The acid–base equilibria of six ACE inhibitors (ACEIs), captopril, cilazapril, enalapril, lisinopril, quinapril, and rami-
pril, were investigated in the presence of micelles of nonionic surfactant Brij 35. The pKa values were potentiometrically
determined at 25 °C and at a constant ionic strength (0.1 M NaCl). The obtained potentiometric data were evaluated in the
computer program Hyperquad. On the basis of the shift in the pKa values (ΔpKa ) determined in micellar media in relation
to the pKa values previously determined in “pure” water, the effect of Brij 35 micelles on ACEIs ionization was estimated.
The presence of nonionic Brij 35 micelles caused a shift in the pKa values of all ionizable groups of the investigated ACEIs
(ΔpKa from − 3.44 to + 1.9) while shifting the protolytic equilibria of both acidic and basic groups toward the molecular
form. The Brij 35 micelles expressed the most pronounced effect on the ionization of captopril among the investigated ACEIs
and stronger effect on the ionization of amino than on the ionization of carboxyl groups. The obtained results suggest that
ionizable functional groups of ACEIs are involved in interactions with palisade layer of nonionic Brij 35 micelles, which
potentially can be considered in physiological conditions. Distribution diagrams of the investigated ACEIs equilibrium
forms as a function of pH indicate that the change in distribution is most strongly expressed in pH range 4–8, which includes
biopharmaceutically important pH values.",
publisher = "Springer",
journal = "Monatshefte für Chemie - Chemical Monthly",
title = "Protolytic equilibria of ACE inhibitors in micellar solution of nonionic surfactant Brij 35",
doi = "10.1007/s00706-023-03059-2"
}

Popović‑Nikolić, M., Nikolić, K.,& Popović, G.. (2023). Protolytic equilibria of ACE inhibitors in micellar solution of nonionic surfactant Brij 35. in Monatshefte für Chemie - Chemical Monthly
Springer..
https://doi.org/10.1007/s00706-023-03059-2

Popović‑Nikolić M, Nikolić K, Popović G. Protolytic equilibria of ACE inhibitors in micellar solution of nonionic surfactant Brij 35. in Monatshefte für Chemie - Chemical Monthly. 2023;.
doi:10.1007/s00706-023-03059-2 .

Popović‑Nikolić, Marija, Nikolić, Katarina, Popović, Gordana, "Protolytic equilibria of ACE inhibitors in micellar solution of nonionic surfactant Brij 35" in Monatshefte für Chemie - Chemical Monthly (2023),
https://doi.org/10.1007/s00706-023-03059-2 . .

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 . .

TY  - JOUR
AU  - Đoković, Nemanja
AU  - Đurić, Ana
AU  - Ružić, Dušan
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4472
AB  - Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Development of the chemoresistance in the PDAC is one of the key contributors to the poor survival outcomes and the major reason for urgent development of novel pharmacological approaches in a treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC. However, the number of possible combinations of pharmacological agents is too large to be explored experimentally. In respect to the many epigenetic alterations in PDAC, epigenetic drugs including histone deacetylase inhibitors (HDACi) could be seen as the game changers especially in combined therapy settings. In this work, we explored a possibility of using drug-sensitivity data together with the basal gene expression of pancreatic cell lines to predict combinatorial options available for HDACi. Developed bioinformatics screening protocol for predictions of synergistic drug combinations in PDAC identified the sphingolipid signaling pathway with associated downstream effectors as a promising novel targets for future development of multi-target therapeutics or combined therapy with HDACi. Through the experimental validation, we have characterized novel synergism between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, and between HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod.
PB  - MDPI
T2  - Pharmaceuticals
T1  - Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma
VL  - 16
IS  - 2
DO  - 10.3390/ph16020294
ER  - 

@article{
author = "Đoković, Nemanja and Đurić, Ana and Ružić, Dušan and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2023",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies. Development of the chemoresistance in the PDAC is one of the key contributors to the poor survival outcomes and the major reason for urgent development of novel pharmacological approaches in a treatment of PDAC. Systematically tailored combination therapy holds the promise for advancing the treatment of PDAC. However, the number of possible combinations of pharmacological agents is too large to be explored experimentally. In respect to the many epigenetic alterations in PDAC, epigenetic drugs including histone deacetylase inhibitors (HDACi) could be seen as the game changers especially in combined therapy settings. In this work, we explored a possibility of using drug-sensitivity data together with the basal gene expression of pancreatic cell lines to predict combinatorial options available for HDACi. Developed bioinformatics screening protocol for predictions of synergistic drug combinations in PDAC identified the sphingolipid signaling pathway with associated downstream effectors as a promising novel targets for future development of multi-target therapeutics or combined therapy with HDACi. Through the experimental validation, we have characterized novel synergism between HDACi and a Rho-associated protein kinase (ROCK) inhibitor RKI-1447, and between HDACi and a sphingosine 1-phosphate (S1P) receptor agonist fingolimod.",
publisher = "MDPI",
journal = "Pharmaceuticals",
title = "Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma",
volume = "16",
number = "2",
doi = "10.3390/ph16020294"
}

Đoković, N., Đurić, A., Ružić, D., Srdić-Rajić, T.,& Nikolić, K.. (2023). Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma. in Pharmaceuticals
MDPI., 16(2).
https://doi.org/10.3390/ph16020294

Đoković N, Đurić A, Ružić D, Srdić-Rajić T, Nikolić K. Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma. in Pharmaceuticals. 2023;16(2).
doi:10.3390/ph16020294 .

Đoković, Nemanja, Đurić, Ana, Ružić, Dušan, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Correlating Basal Gene Expression across Chemical Sensitivity Data to Screen for Novel Synergistic Interactors of HDAC Inhibitors in Pancreatic Carcinoma" in Pharmaceuticals, 16, no. 2 (2023),
https://doi.org/10.3390/ph16020294 . .

TY  - JOUR
AU  - Đoković, Nemanja
AU  - Rahnasto-Rilla, Minna
AU  - Lougiakis, Nikolas
AU  - Lahtela-Kakkonen, Maija
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4416
AB  - A growing body of preclinical evidence recognized selective sirtuin 2 (SIRT2) inhibitors as novel therapeutics for treatment of age-related diseases. However, none of the SIRT2 inhibitors have reached clinical trials yet. Transformative potential of machine learning (ML) in early stages of drug discovery has been witnessed by widespread adoption of these techniques in recent years. Despite great potential, there is a lack of robust and large-scale ML models for discovery of novel SIRT2 inhibitors. In order to support virtual screening (VS), lead optimization, or facilitate the selection of SIRT2 inhibitors for experimental evaluation, a machine-learning-based tool titled SIRT2i_Predictor was developed. The tool was built on a panel of high-quality ML regression and classification-based models for prediction of inhibitor potency and SIRT1-3 isoform selectivity. State-of-the-art ML algorithms were used to train the models on a large and diverse dataset containing 1797 compounds. Benchmarking against structure-based VS protocol indicated comparable coverage of chemical space with great gain in speed. The tool was applied to screen the in-house database of compounds, corroborating the utility in the prioritization of compounds for costly in vitro screening campaigns. The easy-to-use web-based interface makes SIRT2i_Predictor a convenient tool for the wider community. The SIRT2i_Predictor’s source code is made available online.
PB  - MDPI
T2  - Pharmaceuticals
T1  - SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors
VL  - 16
IS  - 1
DO  - 10.3390/ph16010127
ER  - 

@article{
author = "Đoković, Nemanja and Rahnasto-Rilla, Minna and Lougiakis, Nikolas and Lahtela-Kakkonen, Maija and Nikolić, Katarina",
year = "2023",
abstract = "A growing body of preclinical evidence recognized selective sirtuin 2 (SIRT2) inhibitors as novel therapeutics for treatment of age-related diseases. However, none of the SIRT2 inhibitors have reached clinical trials yet. Transformative potential of machine learning (ML) in early stages of drug discovery has been witnessed by widespread adoption of these techniques in recent years. Despite great potential, there is a lack of robust and large-scale ML models for discovery of novel SIRT2 inhibitors. In order to support virtual screening (VS), lead optimization, or facilitate the selection of SIRT2 inhibitors for experimental evaluation, a machine-learning-based tool titled SIRT2i_Predictor was developed. The tool was built on a panel of high-quality ML regression and classification-based models for prediction of inhibitor potency and SIRT1-3 isoform selectivity. State-of-the-art ML algorithms were used to train the models on a large and diverse dataset containing 1797 compounds. Benchmarking against structure-based VS protocol indicated comparable coverage of chemical space with great gain in speed. The tool was applied to screen the in-house database of compounds, corroborating the utility in the prioritization of compounds for costly in vitro screening campaigns. The easy-to-use web-based interface makes SIRT2i_Predictor a convenient tool for the wider community. The SIRT2i_Predictor’s source code is made available online.",
publisher = "MDPI",
journal = "Pharmaceuticals",
title = "SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors",
volume = "16",
number = "1",
doi = "10.3390/ph16010127"
}

Đoković, N., Rahnasto-Rilla, M., Lougiakis, N., Lahtela-Kakkonen, M.,& Nikolić, K.. (2023). SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors. in Pharmaceuticals
MDPI., 16(1).
https://doi.org/10.3390/ph16010127

Đoković N, Rahnasto-Rilla M, Lougiakis N, Lahtela-Kakkonen M, Nikolić K. SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors. in Pharmaceuticals. 2023;16(1).
doi:10.3390/ph16010127 .

Đoković, Nemanja, Rahnasto-Rilla, Minna, Lougiakis, Nikolas, Lahtela-Kakkonen, Maija, Nikolić, Katarina, "SIRT2i_Predictor: A Machine Learning-Based Tool to Facilitate the Discovery of Novel SIRT2 Inhibitors" in Pharmaceuticals, 16, no. 1 (2023),
https://doi.org/10.3390/ph16010127 . .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2022-10-29
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4737
AB  - Selective histone deacetylase 6 (HDAC6) inhibition with small molecules is regarded as
a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC
inhibitors1. To date, structural motifs that are important for HDAC inhibitory activity
and selectivity are defined as: surface recognition group (CAP group), aliphatic or
aromatic linker and zinc-binding group (ZBG).
Herein, we describe a comprehensive protocol for the computational fragment search of
novel surface-recognition (CAP) groups aimed to design selective Histone Deacetylase
6 (HDAC6) inhibitors (Figure 1)2. Identified heterocyclic CAP group, 1-benzhydryl
piperazine was employed to synthesize novel HDAC inhibitors with small structural
perturbations in the hydrocarbon linker. Enzymatic in vitro HDAC screening identified
two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as
two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker
chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based
molecular modelling.

References
1. J. Amengual, J. Lue, H. Ma, R. Lichtenstein, B. Shah, S. Cremers, S. Jones, A. Sawas,
The Oncologist, 2021, 26(3), 184 e366.
2. D. Ruzic, M. Petkovic, D. Agbaba, A. Ganesan, K. Nikolic, Mol. Inform., 2019, 38(5),
1800083.

Acknowledgments
The authors acknowledge a Ministry of Education, Science and Technological
Development of the Republic of Serbia Faculty of Pharmacy project (451-03-68/2022-
14/200161).
PB  - Serbian Chemical Society and Serbian Young Chemists’ Club
C3  - Serbian Chemical Society and Serbian Young Chemists’ Club, Book of Abstracts
T1  - Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors
IS  - MC OP 01
SP  - 15
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4737
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2022-10-29",
abstract = "Selective histone deacetylase 6 (HDAC6) inhibition with small molecules is regarded as
a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC
inhibitors1. To date, structural motifs that are important for HDAC inhibitory activity
and selectivity are defined as: surface recognition group (CAP group), aliphatic or
aromatic linker and zinc-binding group (ZBG).
Herein, we describe a comprehensive protocol for the computational fragment search of
novel surface-recognition (CAP) groups aimed to design selective Histone Deacetylase
6 (HDAC6) inhibitors (Figure 1)2. Identified heterocyclic CAP group, 1-benzhydryl
piperazine was employed to synthesize novel HDAC inhibitors with small structural
perturbations in the hydrocarbon linker. Enzymatic in vitro HDAC screening identified
two selective HDAC6 inhibitors (6b, IC50 = 186 nM and 9b, IC50 = 31 nM), as well as
two non-selective nanomolar HDAC inhibitors (7b and 8b). The influence of linker
chemistry of synthesized inhibitors on HDAC6 potency was studied using structure-based
molecular modelling.

References
1. J. Amengual, J. Lue, H. Ma, R. Lichtenstein, B. Shah, S. Cremers, S. Jones, A. Sawas,
The Oncologist, 2021, 26(3), 184 e366.
2. D. Ruzic, M. Petkovic, D. Agbaba, A. Ganesan, K. Nikolic, Mol. Inform., 2019, 38(5),
1800083.

Acknowledgments
The authors acknowledge a Ministry of Education, Science and Technological
Development of the Republic of Serbia Faculty of Pharmacy project (451-03-68/2022-
14/200161).",
publisher = "Serbian Chemical Society and Serbian Young Chemists’ Club",
journal = "Serbian Chemical Society and Serbian Young Chemists’ Club, Book of Abstracts",
title = "Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors",
number = "MC OP 01",
pages = "15",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4737"
}

Ružić, D., Đoković, N., Srdić-Rajić, T.,& Nikolić, K.. (2022-10-29). Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors. in Serbian Chemical Society and Serbian Young Chemists’ Club, Book of Abstracts
Serbian Chemical Society and Serbian Young Chemists’ Club.(MC OP 01), 15.
https://hdl.handle.net/21.15107/rcub_farfar_4737

Ružić D, Đoković N, Srdić-Rajić T, Nikolić K. Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors. in Serbian Chemical Society and Serbian Young Chemists’ Club, Book of Abstracts. 2022;(MC OP 01):15.
https://hdl.handle.net/21.15107/rcub_farfar_4737 .

Ružić, Dušan, Đoković, Nemanja, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors" in Serbian Chemical Society and Serbian Young Chemists’ Club, Book of Abstracts, no. MC OP 01 (2022-10-29):15,
https://hdl.handle.net/21.15107/rcub_farfar_4737 .

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 .

TY  - CONF
AU  - Čarapić, Marija
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2022
UR  - https://ernest-gpcr.eu/2nd-transatlantic-eci-gpcr-symposium-july-6-7-2022/
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 .

TY  - CONF
AU  - Čarapić, Marija
AU  - Marković, Bojan
AU  - Petković, Miloš
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
PY  - 2022
UR  - https://ernest-gpcr.eu/2nd-transatlantic-eci-gpcr-symposium-july-6-7-2022/
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 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Gul, Sheraz
AU  - Lahtela‐Kakkonen, Maija
AU  - Ganesan, A.
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4739
PB  - American Chemical Society Division of Medicinal Chemistry
C3  - 37th ACS National Medicinal Chemistry Symposium - American Chemical Society Division of Medicinal Chemistry, Book of Abstracts
T1  - Computer-aided drug design and evaluation of selective inhibitors against cytoplasmic histone deacetylases
SP  - 125
EP  - 125
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4739
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Gul, Sheraz and Lahtela‐Kakkonen, Maija and Ganesan, A. and Nikolić, Katarina",
year = "2022",
publisher = "American Chemical Society Division of Medicinal Chemistry",
journal = "37th ACS National Medicinal Chemistry Symposium - American Chemical Society Division of Medicinal Chemistry, Book of Abstracts",
title = "Computer-aided drug design and evaluation of selective inhibitors against cytoplasmic histone deacetylases",
pages = "125-125",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4739"
}

Ružić, D., Đoković, N., Petković, M., Gul, S., Lahtela‐Kakkonen, M., Ganesan, A.,& Nikolić, K.. (2022). Computer-aided drug design and evaluation of selective inhibitors against cytoplasmic histone deacetylases. in 37th ACS National Medicinal Chemistry Symposium - American Chemical Society Division of Medicinal Chemistry, Book of Abstracts
American Chemical Society Division of Medicinal Chemistry.(P47), 125-125.
https://hdl.handle.net/21.15107/rcub_farfar_4739

Ružić D, Đoković N, Petković M, Gul S, Lahtela‐Kakkonen M, Ganesan A, Nikolić K. Computer-aided drug design and evaluation of selective inhibitors against cytoplasmic histone deacetylases. in 37th ACS National Medicinal Chemistry Symposium - American Chemical Society Division of Medicinal Chemistry, Book of Abstracts. 2022;(P47):125-125.
https://hdl.handle.net/21.15107/rcub_farfar_4739 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Gul, Sheraz, Lahtela‐Kakkonen, Maija, Ganesan, A., Nikolić, Katarina, "Computer-aided drug design and evaluation of selective inhibitors against cytoplasmic histone deacetylases" in 37th ACS National Medicinal Chemistry Symposium - American Chemical Society Division of Medicinal Chemistry, Book of Abstracts, no. P47 (2022):125-125,
https://hdl.handle.net/21.15107/rcub_farfar_4739 .

TY  - CONF
AU  - Radan, Milica
AU  - Đikić, Teodora
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://4gpcrnet.de/program-thursday/
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4738
PB  - 4GPCRnet Symposium,  Leipzig, Germany, 26 - 29 September 2022
C3  - 4GPCRnet Symposium
T1  - Application of computational methods in rational design of multi-target ligands as potential antipsychotics and antidepressants
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4738
ER  - 

@conference{
author = "Radan, Milica and Đikić, Teodora and Nikolić, Katarina",
year = "2022",
publisher = "4GPCRnet Symposium,  Leipzig, Germany, 26 - 29 September 2022",
journal = "4GPCRnet Symposium",
title = "Application of computational methods in rational design of multi-target ligands as potential antipsychotics and antidepressants",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4738"
}

Radan, M., Đikić, T.,& Nikolić, K.. (2022). Application of computational methods in rational design of multi-target ligands as potential antipsychotics and antidepressants. in 4GPCRnet Symposium
4GPCRnet Symposium,  Leipzig, Germany, 26 - 29 September 2022..
https://hdl.handle.net/21.15107/rcub_farfar_4738

Radan M, Đikić T, Nikolić K. Application of computational methods in rational design of multi-target ligands as potential antipsychotics and antidepressants. in 4GPCRnet Symposium. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4738 .

Radan, Milica, Đikić, Teodora, Nikolić, Katarina, "Application of computational methods in rational design of multi-target ligands as potential antipsychotics and antidepressants" in 4GPCRnet Symposium (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4738 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Gul, Sheraz
AU  - Lahtela‐Kakkonen, Maija
AU  - Ganesan, A.
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4763
PB  - European Federation for Medicinal Chemistry and Chemical Biology (EFMC)
PB  - Société de Chimie Thérapeutique (SCT)
C3  - EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
T1  - Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6
SP  - 141
EP  - 141
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4763
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Gul, Sheraz and Lahtela‐Kakkonen, Maija and Ganesan, A. and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2022",
publisher = "European Federation for Medicinal Chemistry and Chemical Biology (EFMC), Société de Chimie Thérapeutique (SCT)",
journal = "EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts",
title = "Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6",
pages = "141-141",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4763"
}

Ružić, D., Đoković, N., Petković, M., Gul, S., Lahtela‐Kakkonen, M., Ganesan, A., Srdić-Rajić, T.,& Nikolić, K.. (2022). Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6. in EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
European Federation for Medicinal Chemistry and Chemical Biology (EFMC)., 141-141.
https://hdl.handle.net/21.15107/rcub_farfar_4763

Ružić D, Đoković N, Petković M, Gul S, Lahtela‐Kakkonen M, Ganesan A, Srdić-Rajić T, Nikolić K. Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6. in EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts. 2022;:141-141.
https://hdl.handle.net/21.15107/rcub_farfar_4763 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Gul, Sheraz, Lahtela‐Kakkonen, Maija, Ganesan, A., Srdić-Rajić, Tatjana, Nikolić, Katarina, "Rational design and in vitro evaluation of selective inhibitors of cytoplasmic histone deacetylases SIRT2 and HDAC6" in EFMC-ISMC, XXVII EFMC International Symposium on Medicinal Chemistry, Book of Abstracts (2022):141-141,
https://hdl.handle.net/21.15107/rcub_farfar_4763 .

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 .

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 .

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 .

TY  - CONF
AU  - Popović-Nikolić, Marija
AU  - Nikolić, Katarina
AU  - Popović, Gordana
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4597
AB  - The knowledge of drugs ionization is necessary for prediction of their pharmacological
behavior and pharmacokinetic parameters (1). However, the distribution of equilibrium forms
could differ from expected one if the estimation is made exclusively based on pKa vales observed
in “pure” water. It is necessary to investigate the ionization of drugs in conditions which is known
to mimic the biological membranes such as the micellar solutions of surfactants (2). The pKa
values of pharmacologically active compounds (antihypertensives, antimicrobial drugs,
antihistamines) have been potentiometrically determined under the same conditions (25 °C, ionic
strength 0.1 M NaCl) with and without micelles, anionic (SDS), cationic (CTAB), nonionic (TX-
100, Brij 35). Experimental results were analyzed in program Hyperquad. Significant shift in
protolytic equilibria (∆pKa) were observed for aliphatic amino (-2.80 to +0.87), aromatic amino (-
1.99 to +1.44), and carboxylic (-0.92 to +1.90) functional groups. The anionic and cationic
expressed higher effect on ionization comparing to nonionic micelles. The presence of micelles
caused the change in distribution of equilibrium forms especially on pH values of
biopharmaceutical importance where the content of ionized form was changed in range from -74%
to +66% comparing to “pure” water. The ionization groups of drugs are involved in interactions
with charged or polar surface of micelles which could be observed in terms of physiological
conditions. Result showed that general pattern of ionization of drugs in micellar media could not
be anticipated so it is necessary to be experimentally investigated for each individual drug.
AB  - Ispitivanje jonizacije lekova neophodno je za predviđanje farmakološkog ponašanja i
farmakokinetičkih parametara (1). Međutim, raspodela ravnotežnih oblika može biti
drugačija od očekivane ako se procena izvodi samo na osnovu pKa vrednosti definisanih
isključivo u “čistoj” vodi. Zato je potrebno ispitati jonizaciju lekova i u uslovima koji
simuliraju prisustvo bioloških membrana, kao što su micelarni rastvori surfaktanata (2). U
ovoj studiji, pKa vrednosti farmakološki aktivnih jedinjenja (antihipertenzivi, antimikrobni
lekovi, antihistaminici), bez i u prisustvu anjonskih (SDS), katjonskih (CTAB) i nejonskih (TX-
100, Brij 35) micela, određene su potenciometrijski, pod istim eksperimentalnim uslovima
(temperatura 25°C i jonska sila 0,1 M NaCl). Eksperimentalni rezultati analizirani su u
programu Hyperquad. Značajna pomeranja protolitičkih ravnoteža (∆pKa) uočena su u
slučaju aromatične amino (od -1,99 do +1,44), alifatične amino (od -2,80 do +0,87) i
karboksilne grupe (od -0,92 do +1,90). Izraženiji uticaj na promenu jonizacije uočen je u
prisustvu anjonskih i katjonskih u odnosu na nejonske micele. Promena raspodele
ravnotežnih oblika u prisustvu micela zapažena je na biofarmaceutski značajnim pH
vrednostima (1,2; 4,5; 6,8; 7,4), pri čemu je sadržaj jonizovanih formi promenjen u opsegu od
-74% do +66% u odnosu na “čistu” vodu. Rezultati pokazuju da se jonizacione grupe lekova
uključuju u interakcije sa polarnom ili naelektrisanom površinom micela što se može
potencijalno razmatrati u kontekstu uticaja na jonizaciju u fiziološkom uslovima. Nije uočen
uopšten obrazac jonizacije lekova u micelarnoj sredini iz čega sledi da je neophodno
eksperimentalno ispitati jonizaciju svakog pojedinačnog jedinjenja u prisustvu micela.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - The ionization of pharmacologically active compounds in the presence of differently charged micelles as biomembrane mimetic systems
T1  - Jonizacija farmakološki aktivnih jedinjenja u micelarnim rastvorima različitog naelektrisanja kao simulirajućih sistema biomembrana
VL  - 72
IS  - 4 suplement
SP  - S530
EP  - S531
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4597
ER  - 

@conference{
author = "Popović-Nikolić, Marija and Nikolić, Katarina and Popović, Gordana",
year = "2022",
abstract = "The knowledge of drugs ionization is necessary for prediction of their pharmacological
behavior and pharmacokinetic parameters (1). However, the distribution of equilibrium forms
could differ from expected one if the estimation is made exclusively based on pKa vales observed
in “pure” water. It is necessary to investigate the ionization of drugs in conditions which is known
to mimic the biological membranes such as the micellar solutions of surfactants (2). The pKa
values of pharmacologically active compounds (antihypertensives, antimicrobial drugs,
antihistamines) have been potentiometrically determined under the same conditions (25 °C, ionic
strength 0.1 M NaCl) with and without micelles, anionic (SDS), cationic (CTAB), nonionic (TX-
100, Brij 35). Experimental results were analyzed in program Hyperquad. Significant shift in
protolytic equilibria (∆pKa) were observed for aliphatic amino (-2.80 to +0.87), aromatic amino (-
1.99 to +1.44), and carboxylic (-0.92 to +1.90) functional groups. The anionic and cationic
expressed higher effect on ionization comparing to nonionic micelles. The presence of micelles
caused the change in distribution of equilibrium forms especially on pH values of
biopharmaceutical importance where the content of ionized form was changed in range from -74%
to +66% comparing to “pure” water. The ionization groups of drugs are involved in interactions
with charged or polar surface of micelles which could be observed in terms of physiological
conditions. Result showed that general pattern of ionization of drugs in micellar media could not
be anticipated so it is necessary to be experimentally investigated for each individual drug., Ispitivanje jonizacije lekova neophodno je za predviđanje farmakološkog ponašanja i
farmakokinetičkih parametara (1). Međutim, raspodela ravnotežnih oblika može biti
drugačija od očekivane ako se procena izvodi samo na osnovu pKa vrednosti definisanih
isključivo u “čistoj” vodi. Zato je potrebno ispitati jonizaciju lekova i u uslovima koji
simuliraju prisustvo bioloških membrana, kao što su micelarni rastvori surfaktanata (2). U
ovoj studiji, pKa vrednosti farmakološki aktivnih jedinjenja (antihipertenzivi, antimikrobni
lekovi, antihistaminici), bez i u prisustvu anjonskih (SDS), katjonskih (CTAB) i nejonskih (TX-
100, Brij 35) micela, određene su potenciometrijski, pod istim eksperimentalnim uslovima
(temperatura 25°C i jonska sila 0,1 M NaCl). Eksperimentalni rezultati analizirani su u
programu Hyperquad. Značajna pomeranja protolitičkih ravnoteža (∆pKa) uočena su u
slučaju aromatične amino (od -1,99 do +1,44), alifatične amino (od -2,80 do +0,87) i
karboksilne grupe (od -0,92 do +1,90). Izraženiji uticaj na promenu jonizacije uočen je u
prisustvu anjonskih i katjonskih u odnosu na nejonske micele. Promena raspodele
ravnotežnih oblika u prisustvu micela zapažena je na biofarmaceutski značajnim pH
vrednostima (1,2; 4,5; 6,8; 7,4), pri čemu je sadržaj jonizovanih formi promenjen u opsegu od
-74% do +66% u odnosu na “čistu” vodu. Rezultati pokazuju da se jonizacione grupe lekova
uključuju u interakcije sa polarnom ili naelektrisanom površinom micela što se može
potencijalno razmatrati u kontekstu uticaja na jonizaciju u fiziološkom uslovima. Nije uočen
uopšten obrazac jonizacije lekova u micelarnoj sredini iz čega sledi da je neophodno
eksperimentalno ispitati jonizaciju svakog pojedinačnog jedinjenja u prisustvu micela.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "The ionization of pharmacologically active compounds in the presence of differently charged micelles as biomembrane mimetic systems, Jonizacija farmakološki aktivnih jedinjenja u micelarnim rastvorima različitog naelektrisanja kao simulirajućih sistema biomembrana",
volume = "72",
number = "4 suplement",
pages = "S530-S531",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4597"
}

Popović-Nikolić, M., Nikolić, K.,& Popović, G.. (2022). The ionization of pharmacologically active compounds in the presence of differently charged micelles as biomembrane mimetic systems. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S530-S531.
https://hdl.handle.net/21.15107/rcub_farfar_4597

Popović-Nikolić M, Nikolić K, Popović G. The ionization of pharmacologically active compounds in the presence of differently charged micelles as biomembrane mimetic systems. in Arhiv za farmaciju. 2022;72(4 suplement):S530-S531.
https://hdl.handle.net/21.15107/rcub_farfar_4597 .

Popović-Nikolić, Marija, Nikolić, Katarina, Popović, Gordana, "The ionization of pharmacologically active compounds in the presence of differently charged micelles as biomembrane mimetic systems" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S530-S531,
https://hdl.handle.net/21.15107/rcub_farfar_4597 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Rahnasto‐Rilla, Minna
AU  - Srdić-Rajić, Tatjana
AU  - Lahtela‐Kakkonen, Maija
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4523
AB  - Inhibitors of sirtuin 2 (SIRT2i) represent a promising group of novel therapeutics in
treatment of the age-related disorders, including carcinomas, neurodegenerative diseases,
metabolic syndrome etc. (1). Despite the promising preclinical results, none of the known
SIRT2i reached clinical trials. One of the main obstacles in the structure-based drug design of
novel SIRT2i represents intricate conformational dynamics of sirtuin 2 (SIRT2) binding
pocket (2). In order to facilitate the discovery of novel SIRT2i, we have developed the
protocol for enhanced sampling of the binding pocket dynamics and validated it by
integration into structure-based virtual screening (SBVS) pipeline for discovery of novel
SIRT2i. Developed protocol relies on well-tempered metadynamics simulations using the set
of pocket-related collective variables derived from time-lagged independent component
analysis (tICA). Our protocol outperformed classical molecular dynamics in search for
alternative conformational states of the binding pocket. Additionally, the protocol was able
to reveal the existence of cryptic subpocket inside SIRT2 binding pocket. To validate our
findings, the protocol was implemented into SBVS which resulted in significant expansion of
SIRT2i chemical space. To further probe the potential of expanded chemical space in
discovery of chemically novel groups of SIRT2i, a few virtual hit molecules were selected and
tested in vitro. Compound NDJ18 was shown to be potent and selective SIRT2i with
anticancer activity on triple-negative breast cancer cell line MDA-MB-231. Experimental
validation supported future generalization of the protocol by application on wider scope of
challenging protein targets.
AB  - Inhibitori sirtuina 2 (SIRT2i) predstavljaju obećavajuću grupu novih terapeutika u
terapiji poremećaja povezanih sa starenjem, poput malignih oboljenja, neurodegenerativnih
oboljenja, metaboličkog sindroma itd. (1). Uprkos obećavajućim rezultatima prekliničkih
ispitivanja, nijedan SIRT2i nije došao do kliničkih studija. Jedna od glavnih prepreka u
strukturno-zavisnom dizajnu novih SIRT2i predstavlja kompleksna konformaciona dinamika
vezivnog mesta sirtuina 2 (SIRT2) (2). U cilju povećanja efikasnosti racionalnog dizajna
novih SIRT2i, razvijen je protokol za poboljšano uzorkovanje konformacione dinamike
vezivnog mesta SIRT2 koji se zasniva na metadinamičkim simulacijama uz set kolektivnih
varijabli izvedenih iz analize nezavisnih komponenti vremenskih zaostataka dinamike
vezivnog mesta (tICA). Razvijeni protokol nadmašio je klasičnu molekulsku dinamiku u
efikasnosti pretrage alternativnih konformacionih stanja vezivnog mesta. Dodatno,
primenom razvijenog protokola otkriveno je postojanje skrivenog džepa unutar vezivnog
mesta SIRT2. U cilju validacije, protokol je implementiran u strukturno-zavisni virtuelni
skrining SIRT2i što je rezultovalo u značajnoj ekspanziji postojećeg hemijskog prostora
SIRT2i. U daljem testiranju potencijala proširenog hemijskog prostora u otkriću potpuno
novih hemijskih skeleta SIRT2i, nekoliko najbolje rangiranih molekula je selektovano i
evaluirano in vitro. Jedinjenje NDJ18 se pokazalo kao potentan i selektivan novi SIRT2i.
Testiranjima na trostruko-negativnoj ćelijskoj liniji kancera dojke MDA-MB-231 utvrđen je
značajan antikancerski potencijal navedenog jedinjenja. Eksperimentalnom validacijom
podržan je dalji razvoj i generalizacija protokola kroz primenu na širem spektru proteinskih
targeta izazovnih sa aspekta tehnika racionalnog dizajna lekova.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign
T1  - Novi protokol za poboljšano uzorkovanje dinamike vezivnih mesta i njegova integracija u virtuelni skrining inhibitora sirtuina 2
VL  - 72
IS  - 4 suplement
SP  - S241
EP  - S242
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4523
ER  - 

@conference{
author = "Đoković, Nemanja and Ružić, Dušan and Rahnasto‐Rilla, Minna and Srdić-Rajić, Tatjana and Lahtela‐Kakkonen, Maija and Nikolić, Katarina",
year = "2022",
abstract = "Inhibitors of sirtuin 2 (SIRT2i) represent a promising group of novel therapeutics in
treatment of the age-related disorders, including carcinomas, neurodegenerative diseases,
metabolic syndrome etc. (1). Despite the promising preclinical results, none of the known
SIRT2i reached clinical trials. One of the main obstacles in the structure-based drug design of
novel SIRT2i represents intricate conformational dynamics of sirtuin 2 (SIRT2) binding
pocket (2). In order to facilitate the discovery of novel SIRT2i, we have developed the
protocol for enhanced sampling of the binding pocket dynamics and validated it by
integration into structure-based virtual screening (SBVS) pipeline for discovery of novel
SIRT2i. Developed protocol relies on well-tempered metadynamics simulations using the set
of pocket-related collective variables derived from time-lagged independent component
analysis (tICA). Our protocol outperformed classical molecular dynamics in search for
alternative conformational states of the binding pocket. Additionally, the protocol was able
to reveal the existence of cryptic subpocket inside SIRT2 binding pocket. To validate our
findings, the protocol was implemented into SBVS which resulted in significant expansion of
SIRT2i chemical space. To further probe the potential of expanded chemical space in
discovery of chemically novel groups of SIRT2i, a few virtual hit molecules were selected and
tested in vitro. Compound NDJ18 was shown to be potent and selective SIRT2i with
anticancer activity on triple-negative breast cancer cell line MDA-MB-231. Experimental
validation supported future generalization of the protocol by application on wider scope of
challenging protein targets., Inhibitori sirtuina 2 (SIRT2i) predstavljaju obećavajuću grupu novih terapeutika u
terapiji poremećaja povezanih sa starenjem, poput malignih oboljenja, neurodegenerativnih
oboljenja, metaboličkog sindroma itd. (1). Uprkos obećavajućim rezultatima prekliničkih
ispitivanja, nijedan SIRT2i nije došao do kliničkih studija. Jedna od glavnih prepreka u
strukturno-zavisnom dizajnu novih SIRT2i predstavlja kompleksna konformaciona dinamika
vezivnog mesta sirtuina 2 (SIRT2) (2). U cilju povećanja efikasnosti racionalnog dizajna
novih SIRT2i, razvijen je protokol za poboljšano uzorkovanje konformacione dinamike
vezivnog mesta SIRT2 koji se zasniva na metadinamičkim simulacijama uz set kolektivnih
varijabli izvedenih iz analize nezavisnih komponenti vremenskih zaostataka dinamike
vezivnog mesta (tICA). Razvijeni protokol nadmašio je klasičnu molekulsku dinamiku u
efikasnosti pretrage alternativnih konformacionih stanja vezivnog mesta. Dodatno,
primenom razvijenog protokola otkriveno je postojanje skrivenog džepa unutar vezivnog
mesta SIRT2. U cilju validacije, protokol je implementiran u strukturno-zavisni virtuelni
skrining SIRT2i što je rezultovalo u značajnoj ekspanziji postojećeg hemijskog prostora
SIRT2i. U daljem testiranju potencijala proširenog hemijskog prostora u otkriću potpuno
novih hemijskih skeleta SIRT2i, nekoliko najbolje rangiranih molekula je selektovano i
evaluirano in vitro. Jedinjenje NDJ18 se pokazalo kao potentan i selektivan novi SIRT2i.
Testiranjima na trostruko-negativnoj ćelijskoj liniji kancera dojke MDA-MB-231 utvrđen je
značajan antikancerski potencijal navedenog jedinjenja. Eksperimentalnom validacijom
podržan je dalji razvoj i generalizacija protokola kroz primenu na širem spektru proteinskih
targeta izazovnih sa aspekta tehnika racionalnog dizajna lekova.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign, Novi protokol za poboljšano uzorkovanje dinamike vezivnih mesta i njegova integracija u virtuelni skrining inhibitora sirtuina 2",
volume = "72",
number = "4 suplement",
pages = "S241-S242",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4523"
}

Đoković, N., Ružić, D., Rahnasto‐Rilla, M., Srdić-Rajić, T., Lahtela‐Kakkonen, M.,& Nikolić, K.. (2022). Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 72(4 suplement), S241-S242.
https://hdl.handle.net/21.15107/rcub_farfar_4523

Đoković N, Ružić D, Rahnasto‐Rilla M, Srdić-Rajić T, Lahtela‐Kakkonen M, Nikolić K. Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign. in Arhiv za farmaciju. 2022;72(4 suplement):S241-S242.
https://hdl.handle.net/21.15107/rcub_farfar_4523 .

Đoković, Nemanja, Ružić, Dušan, Rahnasto‐Rilla, Minna, Srdić-Rajić, Tatjana, Lahtela‐Kakkonen, Maija, Nikolić, Katarina, "Novel protocol for enhanced sampling of binding pocket dynamics and its integration into the sirtuin 2 inhibitors virtual screening campaign" in Arhiv za farmaciju, 72, no. 4 suplement (2022):S241-S242,
https://hdl.handle.net/21.15107/rcub_farfar_4523 .

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 .

TY  - JOUR
AU  - Ružić, Dušan
AU  - Ellinger, Bernhard
AU  - Đoković, Nemanja
AU  - Santibanez, Juan
AU  - Gul, Sheraz
AU  - Beljkaš, Milan
AU  - Đurić, Ana
AU  - Ganesan, Arasu
AU  - Pavić, Aleksandar
AU  - Srdić-Rajić, Tatjana
AU  - Petković, Miloš
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4368
AB  - Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.
PB  - MDPI
T2  - Pharmaceutics
T1  - Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation
VL  - 14
IS  - 12
DO  - 10.3390/pharmaceutics14122600
ER  - 

@article{
author = "Ružić, Dušan and Ellinger, Bernhard and Đoković, Nemanja and Santibanez, Juan and Gul, Sheraz and Beljkaš, Milan and Đurić, Ana and Ganesan, Arasu and Pavić, Aleksandar and Srdić-Rajić, Tatjana and Petković, Miloš and Nikolić, Katarina",
year = "2022",
abstract = "Pharmacological inhibition of histone deacetylase 6 (HDAC6) is an effective therapeutic strategy for cancer and immunological diseases. Most of the previously reported HDAC6 inhibitors have a hydroxamate group as a zinc binding group (ZBG), which coordinates to the catalytic zinc ion of HDAC6. The hydroxamate group is liable to metabolically generate mutagenetic hydroxylamine; therefore, non-hydroxamate HDAC6 inhibitors would be advantageous. In this study, to identify novel non-hydroxamate HDAC6-selective inhibitors, screening of a chemical library and the subsequent structural optimization were performed, which led to the identification of HDAC6-selective inhibitors with 3,3,3-trifluorolactic amide (TFLAM) as a novel ZBG. The identified inhibitor showed potent and selective HDAC6-inhibitory activity in cells and induced regulatory T (Treg) cell differentiation.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation",
volume = "14",
number = "12",
doi = "10.3390/pharmaceutics14122600"
}

Ružić, D., Ellinger, B., Đoković, N., Santibanez, J., Gul, S., Beljkaš, M., Đurić, A., Ganesan, A., Pavić, A., Srdić-Rajić, T., Petković, M.,& Nikolić, K.. (2022). Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation. in Pharmaceutics
MDPI., 14(12).
https://doi.org/10.3390/pharmaceutics14122600

Ružić D, Ellinger B, Đoković N, Santibanez J, Gul S, Beljkaš M, Đurić A, Ganesan A, Pavić A, Srdić-Rajić T, Petković M, Nikolić K. Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation. in Pharmaceutics. 2022;14(12).
doi:10.3390/pharmaceutics14122600 .

Ružić, Dušan, Ellinger, Bernhard, Đoković, Nemanja, Santibanez, Juan, Gul, Sheraz, Beljkaš, Milan, Đurić, Ana, Ganesan, Arasu, Pavić, Aleksandar, Srdić-Rajić, Tatjana, Petković, Miloš, Nikolić, Katarina, "Discovery of 1-Benzhydryl-Piperazine-Based HDAC Inhibitors with Anti-Breast Cancer Activity: Synthesis, Molecular Modeling, In Vitro and In Vivo Biological Evaluation" in Pharmaceutics, 14, no. 12 (2022),
https://doi.org/10.3390/pharmaceutics14122600 . .

TY  - JOUR
AU  - Bulut, Ipek
AU  - Lee, Adam
AU  - Cevatemre, Buse
AU  - Ružić, Dušan
AU  - Belle, Roman
AU  - Kawamura, Akane
AU  - Gul, Sheraz
AU  - Nikolić, Katarina
AU  - Ganesan, A.
AU  - Acilan, Ceyda
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4340
AB  - Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.
PB  - MDPI
T2  - Cancers
T1  - Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells
VL  - 14
IS  - 23
DO  - 10.3390/cancers14236014
ER  - 

@article{
author = "Bulut, Ipek and Lee, Adam and Cevatemre, Buse and Ružić, Dušan and Belle, Roman and Kawamura, Akane and Gul, Sheraz and Nikolić, Katarina and Ganesan, A. and Acilan, Ceyda",
year = "2022",
abstract = "Defects in epigenetic pathways are key drivers of oncogenic cell proliferation. We developed a LSD1/HDAC6 multitargeting inhibitor (iDual), a hydroxamic acid analogue of the clinical candidate LSD1 inhibitor GSK2879552. iDual inhibits both targets with IC50 values of 540, 110, and 290 nM, respectively, against LSD1, HDAC6, and HDAC8. We compared its activity to structurally similar control probes that act by HDAC or LSD1 inhibition alone, as well as an inactive null compound. iDual inhibited the growth of leukemia cell lines at a higher level than GSK2879552 with micromolar IC50 values. Dual engagement with LSD1 and HDAC6 was supported by dose dependent increases in substrate levels, biomarkers, and cellular thermal shift assay. Both histone methylation and acetylation of tubulin were increased, while acetylated histone levels were only mildly affected, indicating selectivity for HDAC6. Downstream gene expression (CD11b, CD86, p21) was also elevated in response to iDual treatment. Remarkably, iDual synergized with doxorubicin, triggering significant levels of apoptosis with a sublethal concentration of the drug. While mechanistic studies did not reveal changes in DNA repair or drug efflux pathways, the expression of AGPAT9, ALOX5, BTG1, HIPK2, IFI44L, and LRP1, previously implicated in doxorubicin sensitivity, was significantly elevated.",
publisher = "MDPI",
journal = "Cancers",
title = "Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells",
volume = "14",
number = "23",
doi = "10.3390/cancers14236014"
}

Bulut, I., Lee, A., Cevatemre, B., Ružić, D., Belle, R., Kawamura, A., Gul, S., Nikolić, K., Ganesan, A.,& Acilan, C.. (2022). Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. in Cancers
MDPI., 14(23).
https://doi.org/10.3390/cancers14236014

Bulut I, Lee A, Cevatemre B, Ružić D, Belle R, Kawamura A, Gul S, Nikolić K, Ganesan A, Acilan C. Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. in Cancers. 2022;14(23).
doi:10.3390/cancers14236014 .

Bulut, Ipek, Lee, Adam, Cevatemre, Buse, Ružić, Dušan, Belle, Roman, Kawamura, Akane, Gul, Sheraz, Nikolić, Katarina, Ganesan, A., Acilan, Ceyda, "Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells" in Cancers, 14, no. 23 (2022),
https://doi.org/10.3390/cancers14236014 . .

TY  - JOUR
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Rahnasto-Rilla, Mina
AU  - Srdić-Rajić, Tatjana
AU  - Lahtela-Kakkonen, Maija
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4102
AB  - Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects. In this study, we propose the protocol for computational simulations of sirtuin 2 (SIRT2) binding pocket dynamics and its integration into the structure-based virtual screening (SBVS) pipeline. Initially, unbiased molecular dynamics simulations of SIRT2:inhibitor complexes were performed using optimized force field parameters of SIRT2 inhibitors. Time-lagged independent component analysis (tICA) was used to design pocket-related collective variables (CVs) for enhanced sampling of SIRT2 pocket dynamics. Metadynamics simulations in the tICA eigenvector space revealed alternative conformational states of the SIRT2 binding pocket and the existence of a cryptic subpocket. Newly identified SIRT2 conformational states outperformed experimentally resolved states in retrospective SBVS validation. After performing prospective SBVS, compounds from the under-represented portions of the SIRT2 inhibitor chemical space were selected for in vitro evaluation. Two compounds, NDJ18 and NDJ85, were identified as potent and selective SIRT2 inhibitors, which validated the in silico protocol and opened up the possibility for generalization and broadening of its application. The anticancer effects of the most potent compound NDJ18 were examined on the triple-negative breast cancer cell line. Results indicated that NDJ18 represents a promising structure suitable for further evaluation.
PB  - American Chemical Society
T2  - Journal of Chemical Information and Modeling
T1  - Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics
VL  - 62
IS  - 10
SP  - 2571
EP  - 2585
DO  - 10.1021/acs.jcim.2c00241
ER  - 

@article{
author = "Đoković, Nemanja and Ružić, Dušan and Rahnasto-Rilla, Mina and Srdić-Rajić, Tatjana and Lahtela-Kakkonen, Maija and Nikolić, Katarina",
year = "2022",
abstract = "Considerations of binding pocket dynamics are one of the crucial aspects of the rational design of binders. Identification of alternative conformational states or cryptic subpockets could lead to the discovery of completely novel groups of the ligands. However, experimental characterization of pocket dynamics, besides being expensive, may not be able to elucidate all of the conformational states relevant for drug discovery projects. In this study, we propose the protocol for computational simulations of sirtuin 2 (SIRT2) binding pocket dynamics and its integration into the structure-based virtual screening (SBVS) pipeline. Initially, unbiased molecular dynamics simulations of SIRT2:inhibitor complexes were performed using optimized force field parameters of SIRT2 inhibitors. Time-lagged independent component analysis (tICA) was used to design pocket-related collective variables (CVs) for enhanced sampling of SIRT2 pocket dynamics. Metadynamics simulations in the tICA eigenvector space revealed alternative conformational states of the SIRT2 binding pocket and the existence of a cryptic subpocket. Newly identified SIRT2 conformational states outperformed experimentally resolved states in retrospective SBVS validation. After performing prospective SBVS, compounds from the under-represented portions of the SIRT2 inhibitor chemical space were selected for in vitro evaluation. Two compounds, NDJ18 and NDJ85, were identified as potent and selective SIRT2 inhibitors, which validated the in silico protocol and opened up the possibility for generalization and broadening of its application. The anticancer effects of the most potent compound NDJ18 were examined on the triple-negative breast cancer cell line. Results indicated that NDJ18 represents a promising structure suitable for further evaluation.",
publisher = "American Chemical Society",
journal = "Journal of Chemical Information and Modeling",
title = "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics",
volume = "62",
number = "10",
pages = "2571-2585",
doi = "10.1021/acs.jcim.2c00241"
}

Đoković, N., Ružić, D., Rahnasto-Rilla, M., Srdić-Rajić, T., Lahtela-Kakkonen, M.,& Nikolić, K.. (2022). Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics. in Journal of Chemical Information and Modeling
American Chemical Society., 62(10), 2571-2585.
https://doi.org/10.1021/acs.jcim.2c00241

Đoković N, Ružić D, Rahnasto-Rilla M, Srdić-Rajić T, Lahtela-Kakkonen M, Nikolić K. Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics. in Journal of Chemical Information and Modeling. 2022;62(10):2571-2585.
doi:10.1021/acs.jcim.2c00241 .

Đoković, Nemanja, Ružić, Dušan, Rahnasto-Rilla, Mina, Srdić-Rajić, Tatjana, Lahtela-Kakkonen, Maija, Nikolić, Katarina, "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics" in Journal of Chemical Information and Modeling, 62, no. 10 (2022):2571-2585,
https://doi.org/10.1021/acs.jcim.2c00241 . .

Milović, E., Petronijević, J., Joksimović, N., Beljkaš, M., Ružić, D., Nikolić, K., Vraneš, M., Tot, A., Đorđić Crnogorac, M., Stanojković, T.,& Janković, N.. (2022). Anticancer evaluation of the selected tetrahydropyrimidines: 3D-QSAR, cytotoxic activities, mechanism of action, DNA, and BSA interactions. in Journal of Molecular Structure
Elsevier B.V.., 1257.
https://doi.org/10.1016/j.molstruc.2022.132621

Milović E, Petronijević J, Joksimović N, Beljkaš M, Ružić D, Nikolić K, Vraneš M, Tot A, Đorđić Crnogorac M, Stanojković T, Janković N. Anticancer evaluation of the selected tetrahydropyrimidines: 3D-QSAR, cytotoxic activities, mechanism of action, DNA, and BSA interactions. in Journal of Molecular Structure. 2022;1257.
doi:10.1016/j.molstruc.2022.132621 .

Milović, Emilija, Petronijević, Jelena, Joksimović, Nenad, Beljkaš, Milan, Ružić, Dušan, Nikolić, Katarina, Vraneš, Milan, Tot, Aleksandar, Đorđić Crnogorac, Marija, Stanojković, Tatjana, Janković, Nenad, "Anticancer evaluation of the selected tetrahydropyrimidines: 3D-QSAR, cytotoxic activities, mechanism of action, DNA, and BSA interactions" in Journal of Molecular Structure, 1257 (2022),
https://doi.org/10.1016/j.molstruc.2022.132621 . .

TY  - JOUR
AU  - Obradović, Darija
AU  - Radan, Milica
AU  - Đikić, Teodora
AU  - Popović-Nikolić, Marija
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4045
AB  - The drug-human serum albumin binding interaction was evaluated on a stationary phase immobilized with human serum albumin using a mixture of phosphate buffer (pH 7.0) and acetonitrile modifier as mobile phase. The 33 compounds that have a wide structural and therapeutic diversity were analyzed by per- forming a large number of experiments. The interaction mechanism was interpreted based on: i) retention characteristics of structurally related compounds, ii) retention modeling, iii) quantitative structure reten- tion relationship (QSRR), and iv) molecular docking. Small structural differences of related compounds (e.g., reflected in different lipophilicity and polarity) have been found to affect their different binding to human serum albumin. It was found that drug retention in HSA column can be successfully described by using the quadratic function. The isocratic (logk(14%)) and extrapolated (b0(LSS)) retention factors showed the highest correlation (r > 0.76) with the constant that defines the binding affinity for human serum albumin (ACD/I- Lab). Therefore, selected chromatographic parameters can demonstrate reliable applicability for rapid screening of drug-plasma protein binding in drug discovery. In QSRR study, the resulting SVM/logk(14%) and MLR/b0(LSS) models display high internal and external predictive power. The constitutional properties (double bonds, aromatic rings, benzyl, allyl, -amino and -sulfur containing functional groups) supported by the charged parts of surface area had a significant impact on human serum albumin-binding affinity, which was also confirmed with molecular docking study. The high structural diversity of the data set provides wide applicability of tested chromatographic conditions and constructed models for defining the phar- macokinetic profile and possible structural modifications that can increase plasma protein binding of newly synthesized, pharmaceutically important compounds.
PB  - Elsevier B.V.
T2  - Journal of Pharmaceutical and Biomedical Analysis
T1  - The evaluation of drug-plasma protein binding interaction on immobilized human serum albumin stationary phase, aided by different computational approaches
VL  - 211
DO  - 10.1016/j.jpba.2022.114593
ER  - 

@article{
author = "Obradović, Darija and Radan, Milica and Đikić, Teodora and Popović-Nikolić, Marija and Oljačić, Slavica and Nikolić, Katarina",
year = "2022",
abstract = "The drug-human serum albumin binding interaction was evaluated on a stationary phase immobilized with human serum albumin using a mixture of phosphate buffer (pH 7.0) and acetonitrile modifier as mobile phase. The 33 compounds that have a wide structural and therapeutic diversity were analyzed by per- forming a large number of experiments. The interaction mechanism was interpreted based on: i) retention characteristics of structurally related compounds, ii) retention modeling, iii) quantitative structure reten- tion relationship (QSRR), and iv) molecular docking. Small structural differences of related compounds (e.g., reflected in different lipophilicity and polarity) have been found to affect their different binding to human serum albumin. It was found that drug retention in HSA column can be successfully described by using the quadratic function. The isocratic (logk(14%)) and extrapolated (b0(LSS)) retention factors showed the highest correlation (r > 0.76) with the constant that defines the binding affinity for human serum albumin (ACD/I- Lab). Therefore, selected chromatographic parameters can demonstrate reliable applicability for rapid screening of drug-plasma protein binding in drug discovery. In QSRR study, the resulting SVM/logk(14%) and MLR/b0(LSS) models display high internal and external predictive power. The constitutional properties (double bonds, aromatic rings, benzyl, allyl, -amino and -sulfur containing functional groups) supported by the charged parts of surface area had a significant impact on human serum albumin-binding affinity, which was also confirmed with molecular docking study. The high structural diversity of the data set provides wide applicability of tested chromatographic conditions and constructed models for defining the phar- macokinetic profile and possible structural modifications that can increase plasma protein binding of newly synthesized, pharmaceutically important compounds.",
publisher = "Elsevier B.V.",
journal = "Journal of Pharmaceutical and Biomedical Analysis",
title = "The evaluation of drug-plasma protein binding interaction on immobilized human serum albumin stationary phase, aided by different computational approaches",
volume = "211",
doi = "10.1016/j.jpba.2022.114593"
}

Obradović, D., Radan, M., Đikić, T., Popović-Nikolić, M., Oljačić, S.,& Nikolić, K.. (2022). The evaluation of drug-plasma protein binding interaction on immobilized human serum albumin stationary phase, aided by different computational approaches. in Journal of Pharmaceutical and Biomedical Analysis
Elsevier B.V.., 211.
https://doi.org/10.1016/j.jpba.2022.114593

Obradović D, Radan M, Đikić T, Popović-Nikolić M, Oljačić S, Nikolić K. The evaluation of drug-plasma protein binding interaction on immobilized human serum albumin stationary phase, aided by different computational approaches. in Journal of Pharmaceutical and Biomedical Analysis. 2022;211.
doi:10.1016/j.jpba.2022.114593 .

Obradović, Darija, Radan, Milica, Đikić, Teodora, Popović-Nikolić, Marija, Oljačić, Slavica, Nikolić, Katarina, "The evaluation of drug-plasma protein binding interaction on immobilized human serum albumin stationary phase, aided by different computational approaches" in Journal of Pharmaceutical and Biomedical Analysis, 211 (2022),
https://doi.org/10.1016/j.jpba.2022.114593 . .

TY  - JOUR
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Srdić-Rajić, Tatjana
AU  - Echeverria, Cesar
AU  - Nikolić, Katarina
AU  - Santibanez, Juan
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4025
AB  - The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.
PB  - MDPI
T2  - Pharmaceutics
T1  - Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention
VL  - 14
IS  - 1
DO  - 10.3390/pharmaceutics14010209
ER  - 

@article{
author = "Ružić, Dušan and Đoković, Nemanja and Srdić-Rajić, Tatjana and Echeverria, Cesar and Nikolić, Katarina and Santibanez, Juan",
year = "2022",
abstract = "The dysregulation of gene expression is a critical event involved in all steps of tumorigenesis. Aberrant histone and non-histone acetylation modifications of gene expression due to the abnormal activation of histone deacetylases (HDAC) have been reported in hematologic and solid types of cancer. In this sense, the cancer-associated epigenetic alterations are promising targets for anticancer therapy and chemoprevention. HDAC inhibitors (HDACi) induce histone hyperacetylation within target proteins, altering cell cycle and proliferation, cell differentiation, and the regulation of cell death programs. Over the last three decades, an increasing number of synthetic and naturally derived compounds, such as dietary-derived products, have been demonstrated to act as HDACi and have provided biological and molecular insights with regard to the role of HDAC in cancer. The first part of this review is focused on the biological roles of the Zinc-dependent HDAC family in malignant diseases. Accordingly, the small-molecules and natural products such as HDACi are described in terms of cancer therapy and chemoprevention. Furthermore, structural considerations are included to improve the HDACi selectivity and combinatory potential with other specific targeting agents in bifunctional inhibitors and proteolysis targeting chimeras. Additionally, clinical trials that combine HDACi with current therapies are discussed, which may open new avenues in terms of the feasibility of HDACi’s future clinical applications in precision cancer therapies.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention",
volume = "14",
number = "1",
doi = "10.3390/pharmaceutics14010209"
}

Ružić, D., Đoković, N., Srdić-Rajić, T., Echeverria, C., Nikolić, K.,& Santibanez, J.. (2022). Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention. in Pharmaceutics
MDPI., 14(1).
https://doi.org/10.3390/pharmaceutics14010209

Ružić D, Đoković N, Srdić-Rajić T, Echeverria C, Nikolić K, Santibanez J. Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention. in Pharmaceutics. 2022;14(1).
doi:10.3390/pharmaceutics14010209 .

Ružić, Dušan, Đoković, Nemanja, Srdić-Rajić, Tatjana, Echeverria, Cesar, Nikolić, Katarina, Santibanez, Juan, "Targeting Histone Deacetylases: Opportunities for Cancer Treatment and Chemoprevention" in Pharmaceutics, 14, no. 1 (2022),
https://doi.org/10.3390/pharmaceutics14010209 . .

TY  - JOUR
AU  - Radan, Milica
AU  - Đikić, Teodora
AU  - Obradović, Darija
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3989
AB  - Permeability assessment of small molecules through the blood-brain barrier (BBB) plays a significant role in the development of effective central nervous system (CNS) drug candidates. Since in vivo methods for BBB permeability estimation require a lot of time and resources, in silico and in vitro approaches are becoming increasingly popular nowadays for faster and more economical predictions in early phases of drug discovery. In this work, through application of in vitro parallel artificial membrane permeability assay (PAMPA-BBB) and in silico computational methods we aimed to examine the passive permeability of eighteen compounds, which affect serotonin and dopamine levels in the CNS. The data set was consisted of novel six human dopamine transporter (hDAT) substrates that were previously identified as the most promising lead compounds for further optimisation to achieve neuroprotective effect, twelve approved CNS drugs, and their related compounds. Firstly, PAMPA methods was used to experimentally determine effective BBB permeability (Pe) for all studied compounds and obtained results were further submitted for quantitative structure permeability relationship (QSPR) analysis. QSPR models were built by using three different statistical methods: stepwise multiple linear regression (MLR), partial least square (PLS), and support-vector machine (SVM), while their predictive capability was tested through internal and external validation. Obtained statistical parameters (MLR- R2pred=-0.10; PLS- R2pred=0.64, r2m=0.69, r/2m=0.44; SVM- R2pred=0.57, r2m=0.72, r/2m=0.55) indicated that the SVM model is superior over others. The most important molecular descriptors (H0p and SolvEMt_3D) were identified and used to propose structural modifications of the examined compounds in order to improve their BBB permeability. Moreover, steered molecular dynamics (SMD) simulation was employed to comprehensively investigate the permeability pathway of compounds through a lipid bilayer. Taken together, the created QSPR model could be used as a reliable and fast pre-screening tool for BBB permeability prediction of structurally related CNS compounds, while performed MD simulations provide a good foundation for future in silico examination.
PB  - Elsevier B.V.
T2  - European Journal of Pharmaceutical Sciences
T1  - Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates
VL  - 168
DO  - 10.1016/j.ejps.2021.106056
ER  - 

@article{
author = "Radan, Milica and Đikić, Teodora and Obradović, Darija and Nikolić, Katarina",
year = "2022",
abstract = "Permeability assessment of small molecules through the blood-brain barrier (BBB) plays a significant role in the development of effective central nervous system (CNS) drug candidates. Since in vivo methods for BBB permeability estimation require a lot of time and resources, in silico and in vitro approaches are becoming increasingly popular nowadays for faster and more economical predictions in early phases of drug discovery. In this work, through application of in vitro parallel artificial membrane permeability assay (PAMPA-BBB) and in silico computational methods we aimed to examine the passive permeability of eighteen compounds, which affect serotonin and dopamine levels in the CNS. The data set was consisted of novel six human dopamine transporter (hDAT) substrates that were previously identified as the most promising lead compounds for further optimisation to achieve neuroprotective effect, twelve approved CNS drugs, and their related compounds. Firstly, PAMPA methods was used to experimentally determine effective BBB permeability (Pe) for all studied compounds and obtained results were further submitted for quantitative structure permeability relationship (QSPR) analysis. QSPR models were built by using three different statistical methods: stepwise multiple linear regression (MLR), partial least square (PLS), and support-vector machine (SVM), while their predictive capability was tested through internal and external validation. Obtained statistical parameters (MLR- R2pred=-0.10; PLS- R2pred=0.64, r2m=0.69, r/2m=0.44; SVM- R2pred=0.57, r2m=0.72, r/2m=0.55) indicated that the SVM model is superior over others. The most important molecular descriptors (H0p and SolvEMt_3D) were identified and used to propose structural modifications of the examined compounds in order to improve their BBB permeability. Moreover, steered molecular dynamics (SMD) simulation was employed to comprehensively investigate the permeability pathway of compounds through a lipid bilayer. Taken together, the created QSPR model could be used as a reliable and fast pre-screening tool for BBB permeability prediction of structurally related CNS compounds, while performed MD simulations provide a good foundation for future in silico examination.",
publisher = "Elsevier B.V.",
journal = "European Journal of Pharmaceutical Sciences",
title = "Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates",
volume = "168",
doi = "10.1016/j.ejps.2021.106056"
}

Radan, M., Đikić, T., Obradović, D.,& Nikolić, K.. (2022). Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates. in European Journal of Pharmaceutical Sciences
Elsevier B.V.., 168.
https://doi.org/10.1016/j.ejps.2021.106056

Radan M, Đikić T, Obradović D, Nikolić K. Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates. in European Journal of Pharmaceutical Sciences. 2022;168.
doi:10.1016/j.ejps.2021.106056 .

Radan, Milica, Đikić, Teodora, Obradović, Darija, Nikolić, Katarina, "Application of in vitro PAMPA technique and in silico computational methods for blood-brain barrier permeability prediction of novel CNS drug candidates" in European Journal of Pharmaceutical Sciences, 168 (2022),
https://doi.org/10.1016/j.ejps.2021.106056 . .