TY  - JOUR
AU  - Beljkaš, Milan
AU  - Ilić, Aleksandra
AU  - Cebzan, Alen
AU  - Radović, Branko
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Nikolić, Katarina
AU  - Oljačić, Slavica
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5339
AB  - Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.
PB  - MDPI
T2  - Pharmaceutics
T1  - Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer
VL  - 15
IS  - 11
DO  - 10.3390/pharmaceutics15112581
ER  - 

@article{
author = "Beljkaš, Milan and Ilić, Aleksandra and Cebzan, Alen and Radović, Branko and Đoković, Nemanja and Ružić, Dušan and Nikolić, Katarina and Oljačić, Slavica",
year = "2023",
abstract = "Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer",
volume = "15",
number = "11",
doi = "10.3390/pharmaceutics15112581"
}

Beljkaš, M., Ilić, A., Cebzan, A., Radović, B., Đoković, N., Ružić, D., Nikolić, K.,& Oljačić, S.. (2023). Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer. in Pharmaceutics
MDPI., 15(11).
https://doi.org/10.3390/pharmaceutics15112581

Beljkaš M, Ilić A, Cebzan A, Radović B, Đoković N, Ružić D, Nikolić K, Oljačić S. Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer. in Pharmaceutics. 2023;15(11).
doi:10.3390/pharmaceutics15112581 .

Beljkaš, Milan, Ilić, Aleksandra, Cebzan, Alen, Radović, Branko, Đoković, Nemanja, Ružić, Dušan, Nikolić, Katarina, Oljačić, Slavica, "Targeting Histone Deacetylases 6 in Dual-Target Therapy of Cancer" in Pharmaceutics, 15, no. 11 (2023),
https://doi.org/10.3390/pharmaceutics15112581 . .

TY  - JOUR
AU  - Bagán, Andrea
AU  - Rodriguez-Arévalo, Sergio
AU  - Taboada-Jara, Teresa
AU  - Griñán-Ferré, Christian
AU  - Pallàs, Mercè
AU  - Brocos-Mosquera, Iria
AU  - Callado, Luis F.
AU  - Morales-García, José A.
AU  - Pérez, Belén
AU  - Diaz, Caridad
AU  - Fernández-Godino, Rosario
AU  - Genilloud, Olga
AU  - Beljkaš, Milan
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
AU  - Escolano, Carmen
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5206
AB  - Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.
PB  - MDPI
T2  - Pharmaceutics
T1  - Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease
VL  - 15
IS  - 10
DO  - 10.3390/pharmaceutics15102381
ER  - 

@article{
author = "Bagán, Andrea and Rodriguez-Arévalo, Sergio and Taboada-Jara, Teresa and Griñán-Ferré, Christian and Pallàs, Mercè and Brocos-Mosquera, Iria and Callado, Luis F. and Morales-García, José A. and Pérez, Belén and Diaz, Caridad and Fernández-Godino, Rosario and Genilloud, Olga and Beljkaš, Milan and Oljačić, Slavica and Nikolić, Katarina and Escolano, Carmen",
year = "2023",
abstract = "Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.",
publisher = "MDPI",
journal = "Pharmaceutics",
title = "Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease",
volume = "15",
number = "10",
doi = "10.3390/pharmaceutics15102381"
}

Bagán, A., Rodriguez-Arévalo, S., Taboada-Jara, T., Griñán-Ferré, C., Pallàs, M., Brocos-Mosquera, I., Callado, L. F., Morales-García, J. A., Pérez, B., Diaz, C., Fernández-Godino, R., Genilloud, O., Beljkaš, M., Oljačić, S., Nikolić, K.,& Escolano, C.. (2023). Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease. in Pharmaceutics
MDPI., 15(10).
https://doi.org/10.3390/pharmaceutics15102381

Bagán A, Rodriguez-Arévalo S, Taboada-Jara T, Griñán-Ferré C, Pallàs M, Brocos-Mosquera I, Callado LF, Morales-García JA, Pérez B, Diaz C, Fernández-Godino R, Genilloud O, Beljkaš M, Oljačić S, Nikolić K, Escolano C. Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease. in Pharmaceutics. 2023;15(10).
doi:10.3390/pharmaceutics15102381 .

Bagán, Andrea, Rodriguez-Arévalo, Sergio, Taboada-Jara, Teresa, Griñán-Ferré, Christian, Pallàs, Mercè, Brocos-Mosquera, Iria, Callado, Luis F., Morales-García, José A., Pérez, Belén, Diaz, Caridad, Fernández-Godino, Rosario, Genilloud, Olga, Beljkaš, Milan, Oljačić, Slavica, Nikolić, Katarina, Escolano, Carmen, "Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease" in Pharmaceutics, 15, no. 10 (2023),
https://doi.org/10.3390/pharmaceutics15102381 . .

TY  - CONF
AU  - Beljkaš, Milan
AU  - Rebić, Jelena
AU  - Radan, Milica
AU  - Đikić, Teodora
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5043
AB  - Rho-associated coiled-coil kinases (ROCKs) are involved in essential
cellular functions such as adhesion, contraction, motility, proliferation, and cell
survival/apoptosis. Four ROCK inhibitors have already been approved by the FDA and
are used to treat glaucoma (ripasudil and netarsudil), cerebral vasospasm (fasudil), and
graft-versus-host disease (belumosudil). Recent studies have focused on exploring the
role of ROCK kinase inhibitors in cancer treatment and the development of new ROCK
inhibitors. The main objective of this study was to identify critical structural features
relevant to the inhibition of ROCK1 using a ligand-based 3D-QSAR (3D quantitative
structure-activity relationship) method. The 3D-QSAR model for ROCK1 was created
and validated using internal and external validation parameters (R2, Q2, R2pred, rm2, r/2m, 𝑟���������𝑚���������
2̅̅̅
and ∆r2m). The main structural features that correlate with the inhibition of ROCK1 were
identified (e.g., heterocycle with hydrogen donor group like nitrogen atom) and further
structural modifications of the ROCK1 inhibitors that contribute to increased activity
were proposed (removal of the amino group of the oxadiazole, modification of the
substituents of the phenyl ring).
PB  - Institute for Information Technologies, University of Kragujevac, Serbia
C3  - 2nd International Conference on Chemo and Bioinformatics, BOOK OF PROOCEEDINGS
T1  - 3D-Quantitative Structure-Activity Relationship and design of novel Rho- associated protein kinases-1 (ROCK1) inhibitors
SP  - 1584
EP  - 1588
DO  - 10.46793/ICCBI23.584B
ER  - 

@conference{
author = "Beljkaš, Milan and Rebić, Jelena and Radan, Milica and Đikić, Teodora and Oljačić, Slavica and Nikolić, Katarina",
year = "2023",
abstract = "Rho-associated coiled-coil kinases (ROCKs) are involved in essential
cellular functions such as adhesion, contraction, motility, proliferation, and cell
survival/apoptosis. Four ROCK inhibitors have already been approved by the FDA and
are used to treat glaucoma (ripasudil and netarsudil), cerebral vasospasm (fasudil), and
graft-versus-host disease (belumosudil). Recent studies have focused on exploring the
role of ROCK kinase inhibitors in cancer treatment and the development of new ROCK
inhibitors. The main objective of this study was to identify critical structural features
relevant to the inhibition of ROCK1 using a ligand-based 3D-QSAR (3D quantitative
structure-activity relationship) method. The 3D-QSAR model for ROCK1 was created
and validated using internal and external validation parameters (R2, Q2, R2pred, rm2, r/2m, 𝑟���������𝑚���������
2̅̅̅
and ∆r2m). The main structural features that correlate with the inhibition of ROCK1 were
identified (e.g., heterocycle with hydrogen donor group like nitrogen atom) and further
structural modifications of the ROCK1 inhibitors that contribute to increased activity
were proposed (removal of the amino group of the oxadiazole, modification of the
substituents of the phenyl ring).",
publisher = "Institute for Information Technologies, University of Kragujevac, Serbia",
journal = "2nd International Conference on Chemo and Bioinformatics, BOOK OF PROOCEEDINGS",
title = "3D-Quantitative Structure-Activity Relationship and design of novel Rho- associated protein kinases-1 (ROCK1) inhibitors",
pages = "1584-1588",
doi = "10.46793/ICCBI23.584B"
}

Beljkaš, M., Rebić, J., Radan, M., Đikić, T., Oljačić, S.,& Nikolić, K.. (2023). 3D-Quantitative Structure-Activity Relationship and design of novel Rho- associated protein kinases-1 (ROCK1) inhibitors. in 2nd International Conference on Chemo and Bioinformatics, BOOK OF PROOCEEDINGS
Institute for Information Technologies, University of Kragujevac, Serbia., 1584-1588.
https://doi.org/10.46793/ICCBI23.584B

Beljkaš M, Rebić J, Radan M, Đikić T, Oljačić S, Nikolić K. 3D-Quantitative Structure-Activity Relationship and design of novel Rho- associated protein kinases-1 (ROCK1) inhibitors. in 2nd International Conference on Chemo and Bioinformatics, BOOK OF PROOCEEDINGS. 2023;:1584-1588.
doi:10.46793/ICCBI23.584B .

Beljkaš, Milan, Rebić, Jelena, Radan, Milica, Đikić, Teodora, Oljačić, Slavica, Nikolić, Katarina, "3D-Quantitative Structure-Activity Relationship and design of novel Rho- associated protein kinases-1 (ROCK1) inhibitors" in 2nd International Conference on Chemo and Bioinformatics, BOOK OF PROOCEEDINGS (2023):1584-1588,
https://doi.org/10.46793/ICCBI23.584B . .

TY  - CONF
AU  - Beljkaš, Milan
AU  - Rebić, Jelena
AU  - Radan, Milica
AU  - Đikić, Teodora
AU  - Oljačić, Slavica
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5041
AB  - Overexpression of Rho-associated protein kinases has been associated with various
diseases, including tumors. None of the approved ROCK inhibitors are used for cancer treatment.
However, some of them have been shown to have anti-tumor potential. The main objective of this
study was to develop novel ROCK1 inhibitors using the structure-based method, molecular
docking, and prediction of pharmacokinetic properties using the ADMET predictor. The key
interactions that strongly correlate with the activity of ROCK1 inhibitors are hydrogen bonds
between amino acid residues Met156, Glu154 and the hinge region of the inhibitors, indicating
possible structural changes in the hinge region of studied compounds. On the other hand, the
lack of interactions between 1,3-benzoxadiol moiety and the enzyme presents a promising
approach for further structural modifications in order to design more effective ROCK1 inhibitors.
All the important interactions between the developed ROCK1 inhibitors and the binding site
of the enzyme were established. They also showed acceptable pharmacokinetic properties and
could be further used for synthesis and evaluation by various biological assays.
PB  - Institute for Information Technologies, University of Kragujevac, Serbia
C3  - 2nd International Conference on Chemo and Bioinformatics ICCBIKG 2023, BOOK OF PROCEEDINGS
T1  - Virtual Docking, design and in silico ADMET profiling of novel Rho- associated protein kinases-1 (ROCK1) inhibitors
SP  - 1589
EP  - 1592
DO  - 10.46793/ICCBI23.589B
ER  - 

@conference{
author = "Beljkaš, Milan and Rebić, Jelena and Radan, Milica and Đikić, Teodora and Oljačić, Slavica and Nikolić, Katarina",
year = "2023",
abstract = "Overexpression of Rho-associated protein kinases has been associated with various
diseases, including tumors. None of the approved ROCK inhibitors are used for cancer treatment.
However, some of them have been shown to have anti-tumor potential. The main objective of this
study was to develop novel ROCK1 inhibitors using the structure-based method, molecular
docking, and prediction of pharmacokinetic properties using the ADMET predictor. The key
interactions that strongly correlate with the activity of ROCK1 inhibitors are hydrogen bonds
between amino acid residues Met156, Glu154 and the hinge region of the inhibitors, indicating
possible structural changes in the hinge region of studied compounds. On the other hand, the
lack of interactions between 1,3-benzoxadiol moiety and the enzyme presents a promising
approach for further structural modifications in order to design more effective ROCK1 inhibitors.
All the important interactions between the developed ROCK1 inhibitors and the binding site
of the enzyme were established. They also showed acceptable pharmacokinetic properties and
could be further used for synthesis and evaluation by various biological assays.",
publisher = "Institute for Information Technologies, University of Kragujevac, Serbia",
journal = "2nd International Conference on Chemo and Bioinformatics ICCBIKG 2023, BOOK OF PROCEEDINGS",
title = "Virtual Docking, design and in silico ADMET profiling of novel Rho- associated protein kinases-1 (ROCK1) inhibitors",
pages = "1589-1592",
doi = "10.46793/ICCBI23.589B"
}

Beljkaš, M., Rebić, J., Radan, M., Đikić, T., Oljačić, S.,& Nikolić, K.. (2023). Virtual Docking, design and in silico ADMET profiling of novel Rho- associated protein kinases-1 (ROCK1) inhibitors. in 2nd International Conference on Chemo and Bioinformatics ICCBIKG 2023, BOOK OF PROCEEDINGS
Institute for Information Technologies, University of Kragujevac, Serbia., 1589-1592.
https://doi.org/10.46793/ICCBI23.589B

Beljkaš M, Rebić J, Radan M, Đikić T, Oljačić S, Nikolić K. Virtual Docking, design and in silico ADMET profiling of novel Rho- associated protein kinases-1 (ROCK1) inhibitors. in 2nd International Conference on Chemo and Bioinformatics ICCBIKG 2023, BOOK OF PROCEEDINGS. 2023;:1589-1592.
doi:10.46793/ICCBI23.589B .

Beljkaš, Milan, Rebić, Jelena, Radan, Milica, Đikić, Teodora, Oljačić, Slavica, Nikolić, Katarina, "Virtual Docking, design and in silico ADMET profiling of novel Rho- associated protein kinases-1 (ROCK1) inhibitors" in 2nd International Conference on Chemo and Bioinformatics ICCBIKG 2023, BOOK OF PROCEEDINGS (2023):1589-1592,
https://doi.org/10.46793/ICCBI23.589B . .

TY  - CONF
AU  - Beljkaš, Milan
AU  - Petković, Miloš
AU  - Nikolić, Katarina
AU  - Oljačić, Slavica
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5005
AB  - Histone deacetylases (HDACs) belong to a family of epigenetic enzymes that has 18 different
isoforms and play an important role in the development and progression of various tumors.
To date, five histone deacetylase inhibitors have been approved by the FDA, and are used
to treat multiple myeloma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and
breast cancer (estrogen and/or progesterone positive) [1]. All of them are non-selective.
Therefore, their safety profile is poor and their efficacy is low in single therapy. One of our
previous research projects demonstrated the synergistic effect of HDAC inhibitors and
inhibitors of Rho-associated protein kinases (ROCK) in the treatment of pancreatic ductal
adenocarcinoma (PDAC) [2]. This finding led us to design of the dual HDAC/ROCK inhibitors
with potential effects on PDAC by using structure-based molecular docking method.
Molecular docking study was performed using GOLD software. The crystal structures of
ROCK1 (PDB: 6E9W), ROCK2 (PDB: 7JNT), HDAC1 (PDB: 5ICN), and HDAC6 (PDB: 5EDU)
enzymes were downloaded from the Protein Data Bank (PDB). The enzymes were prepared
for docking study using the online software Play Molecule-ProteinPrepare. The structures
of the ROCK1, ROCK2, HDAC1 and HDAC6 inhibitors with their pIC50 values were obtained
from the ChEMBL database. The dominant microspecies of all compounds at physiological
pH were selected by Marvin Sketch Sketch 6.1.0 program and their further geometrical
optimization were performed using the PM3 semi-empirical method and the Hartree-Fock
method with 3-21G basis set.
The virtual docking procedures for all four enzymes were validated and the calculated RMSD
values were below 2Å. The critical parts of the structures that establish the interactions
crucial for the inhibition of HDAC1, HDAC6, ROCK1, and ROCK2 were identified. Based on
the obtained resultsdual HDAC/ROCK inhibitors were designed and evaluated by validated
docking procedures and in silico ADMET profiling.
Taking into account all these findings, the most active compounds are selected and will be
further synthesized and evaluated using in vitro enzyme and cell tests.
PB  - International Association of Physical Chemists
C3  - 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
T1  - Virtual docking and design of novel Histone deacetylase and Rho- associated protein kinases dual inhibitors (HDAC/ROCKs)
SP  - 46
EP  - 46
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5005
ER  - 

@conference{
author = "Beljkaš, Milan and Petković, Miloš and Nikolić, Katarina and Oljačić, Slavica",
year = "2023",
abstract = "Histone deacetylases (HDACs) belong to a family of epigenetic enzymes that has 18 different
isoforms and play an important role in the development and progression of various tumors.
To date, five histone deacetylase inhibitors have been approved by the FDA, and are used
to treat multiple myeloma, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and
breast cancer (estrogen and/or progesterone positive) [1]. All of them are non-selective.
Therefore, their safety profile is poor and their efficacy is low in single therapy. One of our
previous research projects demonstrated the synergistic effect of HDAC inhibitors and
inhibitors of Rho-associated protein kinases (ROCK) in the treatment of pancreatic ductal
adenocarcinoma (PDAC) [2]. This finding led us to design of the dual HDAC/ROCK inhibitors
with potential effects on PDAC by using structure-based molecular docking method.
Molecular docking study was performed using GOLD software. The crystal structures of
ROCK1 (PDB: 6E9W), ROCK2 (PDB: 7JNT), HDAC1 (PDB: 5ICN), and HDAC6 (PDB: 5EDU)
enzymes were downloaded from the Protein Data Bank (PDB). The enzymes were prepared
for docking study using the online software Play Molecule-ProteinPrepare. The structures
of the ROCK1, ROCK2, HDAC1 and HDAC6 inhibitors with their pIC50 values were obtained
from the ChEMBL database. The dominant microspecies of all compounds at physiological
pH were selected by Marvin Sketch Sketch 6.1.0 program and their further geometrical
optimization were performed using the PM3 semi-empirical method and the Hartree-Fock
method with 3-21G basis set.
The virtual docking procedures for all four enzymes were validated and the calculated RMSD
values were below 2Å. The critical parts of the structures that establish the interactions
crucial for the inhibition of HDAC1, HDAC6, ROCK1, and ROCK2 were identified. Based on
the obtained resultsdual HDAC/ROCK inhibitors were designed and evaluated by validated
docking procedures and in silico ADMET profiling.
Taking into account all these findings, the most active compounds are selected and will be
further synthesized and evaluated using in vitro enzyme and cell tests.",
publisher = "International Association of Physical Chemists",
journal = "10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6",
title = "Virtual docking and design of novel Histone deacetylase and Rho- associated protein kinases dual inhibitors (HDAC/ROCKs)",
pages = "46-46",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5005"
}

Beljkaš, M., Petković, M., Nikolić, K.,& Oljačić, S.. (2023). Virtual docking and design of novel Histone deacetylase and Rho- associated protein kinases dual inhibitors (HDAC/ROCKs). in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6
International Association of Physical Chemists., 46-46.
https://hdl.handle.net/21.15107/rcub_farfar_5005

Beljkaš M, Petković M, Nikolić K, Oljačić S. Virtual docking and design of novel Histone deacetylase and Rho- associated protein kinases dual inhibitors (HDAC/ROCKs). in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6. 2023;:46-46.
https://hdl.handle.net/21.15107/rcub_farfar_5005 .

Beljkaš, Milan, Petković, Miloš, Nikolić, Katarina, Oljačić, Slavica, "Virtual docking and design of novel Histone deacetylase and Rho- associated protein kinases dual inhibitors (HDAC/ROCKs)" in 10th IAPC Meeting Tenth World Conference on Physico-Chemical Methods in Drug Discovery & Sixth World Conference on ADMET and DMPK Belgrade, Serbia, September 4-6 (2023):46-46,
https://hdl.handle.net/21.15107/rcub_farfar_5005 .

TY  - JOUR
AU  - Milović, Emilija
AU  - Petronijević, Jelena
AU  - Joksimović, Nenad
AU  - Beljkaš, Milan
AU  - Ružić, Dušan
AU  - Nikolić, Katarina
AU  - Vraneš, Milan
AU  - Tot, Aleksandar
AU  - Đorđić Crnogorac, Marija
AU  - Stanojković, Tatjana
AU  - Janković, Nenad
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4058
AB  - Selected tetrahydropyrimidines (THPMs) were investigated by means of cytotoxic activities on selected cancer (HeLa, A549, and LS174) and non-cancerous cell lines (MRC-5). Among evaluated compounds, two of them ( B7 and B8 ) showed good cytotoxic activity on the tested cell lines and were selected for fur- ther evaluation that included mechanism of action, DNA and BSA interactions and molecular docking study. Calculated parameters from fluorescence quenching studies indicated that B7 and B8 bind on mi- nor groove of DNA and have great ability to bind on carrier protein. Three-dimensional quantitative struc- ture anti-HeLa activity study was performed with data set of THPMs. Molecular Interaction Fields were used to derive Grid independent descriptors (GRIND), as independent variables in Pentacle software. The quality and predictive capacity of the model was proved by internal statistical parameters: R 2 = 0.992, Q 2 = 0.51, as well as external parameters such as R 2 pred = 0.804 and r m 2 , r / 2 m and r 2 m , that were higher than 0.5. The structural determinants significant for anti-HeLa activity of compounds were identified by using developed 3D-QSAR model. Interpretation of the most impactful GRIND variables on the anti-HeLa activity generated several hypotheses for design of novel and more potent anti-HeLa tetrahydropyrim- idines. Additional molecular targets for the most active synthesized derivatives ( B7 and B8 ) are predicted by use of online web-based tool-SwissTargetPrediction.
PB  - Elsevier B.V.
T2  - Journal of Molecular Structure
T1  - Anticancer evaluation of the selected tetrahydropyrimidines: 3D-QSAR, cytotoxic activities, mechanism of action, DNA, and BSA interactions
VL  - 1257
DO  - 10.1016/j.molstruc.2022.132621
ER  - 

@article{
author = "Milović, Emilija and Petronijević, Jelena and Joksimović, Nenad and Beljkaš, Milan and Ružić, Dušan and Nikolić, Katarina and Vraneš, Milan and Tot, Aleksandar and Đorđić Crnogorac, Marija and Stanojković, Tatjana and Janković, Nenad",
year = "2022",
abstract = "Selected tetrahydropyrimidines (THPMs) were investigated by means of cytotoxic activities on selected cancer (HeLa, A549, and LS174) and non-cancerous cell lines (MRC-5). Among evaluated compounds, two of them ( B7 and B8 ) showed good cytotoxic activity on the tested cell lines and were selected for fur- ther evaluation that included mechanism of action, DNA and BSA interactions and molecular docking study. Calculated parameters from fluorescence quenching studies indicated that B7 and B8 bind on mi- nor groove of DNA and have great ability to bind on carrier protein. Three-dimensional quantitative struc- ture anti-HeLa activity study was performed with data set of THPMs. Molecular Interaction Fields were used to derive Grid independent descriptors (GRIND), as independent variables in Pentacle software. The quality and predictive capacity of the model was proved by internal statistical parameters: R 2 = 0.992, Q 2 = 0.51, as well as external parameters such as R 2 pred = 0.804 and r m 2 , r / 2 m and r 2 m , that were higher than 0.5. The structural determinants significant for anti-HeLa activity of compounds were identified by using developed 3D-QSAR model. Interpretation of the most impactful GRIND variables on the anti-HeLa activity generated several hypotheses for design of novel and more potent anti-HeLa tetrahydropyrim- idines. Additional molecular targets for the most active synthesized derivatives ( B7 and B8 ) are predicted by use of online web-based tool-SwissTargetPrediction.",
publisher = "Elsevier B.V.",
journal = "Journal of Molecular Structure",
title = "Anticancer evaluation of the selected tetrahydropyrimidines: 3D-QSAR, cytotoxic activities, mechanism of action, DNA, and BSA interactions",
volume = "1257",
doi = "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.. (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  - 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  - Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.
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 = "Isoform-selective histone deacetylase (HDAC) inhibition is promoted as a rational strategy to develop safer anti-cancer drugs compared to non-selective HDAC inhibitors. Despite this presumed benefit, considerably more non-selective HDAC inhibitors have undergone clinical trials. In this report, we detail the design and discovery of potent HDAC inhibitors, with 1-benzhydryl piperazine as a surface recognition group, that differ in hydrocarbon linker. In vitro HDAC screening identified two selective HDAC6 inhibitors with nanomolar IC50 values, as well as two non-selective nanomolar HDAC inhibitors. Structure-based molecular modeling was employed to study the influence of linker chemistry of synthesized inhibitors on HDAC6 potency. The breast cancer cell lines (MDA-MB-231 and MCF-7) were used to evaluate compound-mediated in vitro anti-cancer, anti-migratory, and anti-invasive activities. Experiments on the zebrafish MDA-MB-231 xenograft model revealed that a novel non-selective HDAC inhibitor with a seven-carbon-atom linker exhibits potent anti-tumor, anti-metastatic, and anti-angiogenic effects when tested at low micromolar concentrations.",
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  - CONF
AU  - Nikolić, Katarina
AU  - Ružić, Dušan
AU  - Beljkaš, Milan
AU  - Petković, Miloš
AU  - Gul, Sheraz
AU  - Santibanez, Juan
AU  - Srdić Rajić, Tatjana
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4928
AB  - Academia and industry make an extensive effort to discover selective histone deacetylase 6 inhibitors (HDAC6i) which could be delivered to the patients. These attempts are partially obscured by inconsistency in preclinical data regarding the cellular and biochemical changes upon treatment of solid tumours with HDAC6i. In this study, we present computational design, synthesis of three novel HDAC6 inhibitors along with their in vitro pharmacological profile against zinc-dependent HDACs. The in vitro anticancer effects of the synthesized compounds were examined on four types of cancer cell lines, human breast cancer cell lines (MDA-MB-231 and MCF-7) as well as human melanoma cells (A-375 and 518A2). It was found that the synthesized compounds induce apoptosis in high concentrations (IC50 >30 μM) nonetheless, the observed morphological changes of studied cell lines during cell viability assay prompted us to examine their antimetastatic properties. Novel compound MBDR-4 significantly reduces migration and invasiveness of the MDA-MB-231 and A375 cancer cell lines at subapoptotic concentration (5 μM), which open new avenues for redirecting drug development of selective HDAC6 inhibitors as adjuvant chemotherapeutics, with antimetastatic effects.
AB  - Истраживачи тренутно улажу велике напоре у испитивање селективних
инхибитора хистон деацетилазе 6 (HDAC6i) 1,2 који би могли да нађу клиничку
примену 3 . Ова истраживања су делимично отежана услед неконзистентних
преклиничких резултата о ћелијским и биохемијским променама након
третмана солидних тумора HDAC6i(4,5). Наша студија обухвата компјутерски дизајн и синтезу три нова HDAC6
инхибитора, заједно са in vitro ензимским испитивањем активности на
сродним изоформама HDAC ензимима. Антинеопластичан ефекат синтетисаних једињења је испитан in vitro на четири типа ћелија карцинома,
хуманим ћелијама карцинома дојке (MDA-MB-231 и MCF-7) и хуманим ћелијама меланома (A-375 и 518A2). Утврђено је да синтетисана једињења
индукују апоптозу при високим концентрацијама (IC 50 >30 μM). Истовремено је уочено да ова једињења доводе и до морфолошких промена на третираним ћелијама током извођења теста виабилности што нас је усмерило ка испитивању њихових антиметастатских особина. Једињење MBDR-4
снажно инхибира миграцију и инвазивност MDA-MB-231 и A375 ћелија канцера на субапоптотској концентрацији (5 μM), што отвара нове могућности
за истраживање селективних HDAC6 инхибитора као адјувантних хемотерапеутика са антиметастатским ефектом.
PB  - Serbian Medical Society Oncology Section
C3  - 56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia
T1  - Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?
T1  - Постоји ли граница између цитотоксичног и
антиметастатског ефекта селективних инхибитора
хистон деацетилазе 6 код солидних тумора?
SP  - 264
EP  - 266
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4928
ER  - 

@conference{
author = "Nikolić, Katarina and Ružić, Dušan and Beljkaš, Milan and Petković, Miloš and Gul, Sheraz and Santibanez, Juan and Srdić Rajić, Tatjana",
year = "2019",
abstract = "Academia and industry make an extensive effort to discover selective histone deacetylase 6 inhibitors (HDAC6i) which could be delivered to the patients. These attempts are partially obscured by inconsistency in preclinical data regarding the cellular and biochemical changes upon treatment of solid tumours with HDAC6i. In this study, we present computational design, synthesis of three novel HDAC6 inhibitors along with their in vitro pharmacological profile against zinc-dependent HDACs. The in vitro anticancer effects of the synthesized compounds were examined on four types of cancer cell lines, human breast cancer cell lines (MDA-MB-231 and MCF-7) as well as human melanoma cells (A-375 and 518A2). It was found that the synthesized compounds induce apoptosis in high concentrations (IC50 >30 μM) nonetheless, the observed morphological changes of studied cell lines during cell viability assay prompted us to examine their antimetastatic properties. Novel compound MBDR-4 significantly reduces migration and invasiveness of the MDA-MB-231 and A375 cancer cell lines at subapoptotic concentration (5 μM), which open new avenues for redirecting drug development of selective HDAC6 inhibitors as adjuvant chemotherapeutics, with antimetastatic effects., Истраживачи тренутно улажу велике напоре у испитивање селективних
инхибитора хистон деацетилазе 6 (HDAC6i) 1,2 који би могли да нађу клиничку
примену 3 . Ова истраживања су делимично отежана услед неконзистентних
преклиничких резултата о ћелијским и биохемијским променама након
третмана солидних тумора HDAC6i(4,5). Наша студија обухвата компјутерски дизајн и синтезу три нова HDAC6
инхибитора, заједно са in vitro ензимским испитивањем активности на
сродним изоформама HDAC ензимима. Антинеопластичан ефекат синтетисаних једињења је испитан in vitro на четири типа ћелија карцинома,
хуманим ћелијама карцинома дојке (MDA-MB-231 и MCF-7) и хуманим ћелијама меланома (A-375 и 518A2). Утврђено је да синтетисана једињења
индукују апоптозу при високим концентрацијама (IC 50 >30 μM). Истовремено је уочено да ова једињења доводе и до морфолошких промена на третираним ћелијама током извођења теста виабилности што нас је усмерило ка испитивању њихових антиметастатских особина. Једињење MBDR-4
снажно инхибира миграцију и инвазивност MDA-MB-231 и A375 ћелија канцера на субапоптотској концентрацији (5 μM), што отвара нове могућности
за истраживање селективних HDAC6 инхибитора као адјувантних хемотерапеутика са антиметастатским ефектом.",
publisher = "Serbian Medical Society Oncology Section",
journal = "56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia",
title = "Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?, Постоји ли граница између цитотоксичног и
антиметастатског ефекта селективних инхибитора
хистон деацетилазе 6 код солидних тумора?",
pages = "264-266",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4928"
}

Nikolić, K., Ružić, D., Beljkaš, M., Petković, M., Gul, S., Santibanez, J.,& Srdić Rajić, T.. (2019). Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?. in 56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia
Serbian Medical Society Oncology Section., 264-266.
https://hdl.handle.net/21.15107/rcub_farfar_4928

Nikolić K, Ružić D, Beljkaš M, Petković M, Gul S, Santibanez J, Srdić Rajić T. Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?. in 56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia. 2019;:264-266.
https://hdl.handle.net/21.15107/rcub_farfar_4928 .

Nikolić, Katarina, Ružić, Dušan, Beljkaš, Milan, Petković, Miloš, Gul, Sheraz, Santibanez, Juan, Srdić Rajić, Tatjana, "Is there a borderline between cytotoxic and antimetastatic effects of selective Histone deacetylase 6 inhibitors in solid malignancies?" in 56th Cancerology week, Hotel Crowne plaza, November, 6 - 9. 2019, Belgrade, Serbia (2019):264-266,
https://hdl.handle.net/21.15107/rcub_farfar_4928 .