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  - CONF
AU  - Ružić, Dušan
AU  - Petković, Miloš
AU  - Đoković, Nemanja
AU  - Santibanez, Juan
AU  - Pavić, Aleksandar
AU  - Ganesan, A.
AU  - Srdić Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5074
AB  - Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that has poor survival rates due to the absence of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In the era of precision oncology, it is recognized that an imbalance in post-translational modifications of histones, such as histone lysine acetylation and deacetylation, is closely linked to tumor initiation and progression. Two groups of enzymes control the reversible nature of histone post-translational acetylation: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Isoform-specific targeting of HDACs is considered a rational strategy to develop safe anticancer therapeutics compared to non-selective HDAC inhibitors. However, non-selective HDAC inhibitors have been more extensively studied in clinical trials. This work presents the design and discovery of potent HDAC inhibitors that selectively target HDAC6 isozyme, using 1-benzhydryl piperazine as a surface recognition group with different hydrocarbon linkers. Through in vitro screening, two HDAC6-selective inhibitors with nanomolar IC50 values and two non-selective HDAC inhibitors were identified. Structure-based molecular modelling was utilized to investigate the impact of linker chemistry on the potency of synthesized inhibitors against HDAC6. The anti-cancer, anti-migratory, and anti-invasive activities of these compounds were evaluated using breast cancer cell lines (MDA-MB-231 and MCF-7). Experiments on a zebrafish MDA-MB-231 xenograft model demonstrated that a novel non-selective HDAC inhibitor (8b) with a seven-carbon-atom linker exhibited potent effects against tumor growth, metastasis, and angiogenesis at low micromolar concentrations.
PB  - Serbian Association on for Cancer Research Belgrade, Serbia
C3  - Oncology
Insights
T1  - Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study
VL  - 1
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5074
ER  - 

@conference{
author = "Ružić, Dušan and Petković, Miloš and Đoković, Nemanja and Santibanez, Juan and Pavić, Aleksandar and Ganesan, A. and Srdić Rajić, Tatjana and Nikolić, Katarina",
year = "2023",
abstract = "Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that has poor survival rates due to the absence of specific molecular markers such as estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). In the era of precision oncology, it is recognized that an imbalance in post-translational modifications of histones, such as histone lysine acetylation and deacetylation, is closely linked to tumor initiation and progression. Two groups of enzymes control the reversible nature of histone post-translational acetylation: histone acetyltransferases (HATs) and histone deacetylases (HDACs). Isoform-specific targeting of HDACs is considered a rational strategy to develop safe anticancer therapeutics compared to non-selective HDAC inhibitors. However, non-selective HDAC inhibitors have been more extensively studied in clinical trials. This work presents the design and discovery of potent HDAC inhibitors that selectively target HDAC6 isozyme, using 1-benzhydryl piperazine as a surface recognition group with different hydrocarbon linkers. Through in vitro screening, two HDAC6-selective inhibitors with nanomolar IC50 values and two non-selective HDAC inhibitors were identified. Structure-based molecular modelling was utilized to investigate the impact of linker chemistry on the potency of synthesized inhibitors against HDAC6. The anti-cancer, anti-migratory, and anti-invasive activities of these compounds were evaluated using breast cancer cell lines (MDA-MB-231 and MCF-7). Experiments on a zebrafish MDA-MB-231 xenograft model demonstrated that a novel non-selective HDAC inhibitor (8b) with a seven-carbon-atom linker exhibited potent effects against tumor growth, metastasis, and angiogenesis at low micromolar concentrations.",
publisher = "Serbian Association on for Cancer Research Belgrade, Serbia",
journal = "Oncology
Insights",
title = "Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study",
volume = "1",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5074"
}

Ružić, D., Petković, M., Đoković, N., Santibanez, J., Pavić, A., Ganesan, A., Srdić Rajić, T.,& Nikolić, K.. (2023). Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study. in Oncology
Insights
Serbian Association on for Cancer Research Belgrade, Serbia., 1.
https://hdl.handle.net/21.15107/rcub_farfar_5074

Ružić D, Petković M, Đoković N, Santibanez J, Pavić A, Ganesan A, Srdić Rajić T, Nikolić K. Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study. in Oncology
Insights. 2023;1.
https://hdl.handle.net/21.15107/rcub_farfar_5074 .

Ružić, Dušan, Petković, Miloš, Đoković, Nemanja, Santibanez, Juan, Pavić, Aleksandar, Ganesan, A., Srdić Rajić, Tatjana, Nikolić, Katarina, "Discovery of novel HDAC inhibitors for therapy of triple-negative breast cancer – preclinical study" in Oncology
Insights, 1 (2023),
https://hdl.handle.net/21.15107/rcub_farfar_5074 .

TY  - CONF
AU  - Borrello, Maria Teresa
AU  - Ružić, Dušan
AU  - Oakley, Fiona
AU  - Nikolić, Katarina
AU  - Mann, Jelena
AU  - Mann, Derek
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4912
PB  - Elsevire
C3  - Journal of Hepatology
T1  - Discovery of novel small molecule inhibitors of HDAC6 that suppress liver fibrosis
VL  - 78
IS  - S1
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4912
ER  - 

@conference{
author = "Borrello, Maria Teresa and Ružić, Dušan and Oakley, Fiona and Nikolić, Katarina and Mann, Jelena and Mann, Derek",
year = "2023",
publisher = "Elsevire",
journal = "Journal of Hepatology",
title = "Discovery of novel small molecule inhibitors of HDAC6 that suppress liver fibrosis",
volume = "78",
number = "S1",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4912"
}

Borrello, M. T., Ružić, D., Oakley, F., Nikolić, K., Mann, J.,& Mann, D.. (2023). Discovery of novel small molecule inhibitors of HDAC6 that suppress liver fibrosis. in Journal of Hepatology
Elsevire., 78(S1).
https://hdl.handle.net/21.15107/rcub_farfar_4912

Borrello MT, Ružić D, Oakley F, Nikolić K, Mann J, Mann D. Discovery of novel small molecule inhibitors of HDAC6 that suppress liver fibrosis. in Journal of Hepatology. 2023;78(S1).
https://hdl.handle.net/21.15107/rcub_farfar_4912 .

Borrello, Maria Teresa, Ružić, Dušan, Oakley, Fiona, Nikolić, Katarina, Mann, Jelena, Mann, Derek, "Discovery of novel small molecule inhibitors of HDAC6 that suppress liver fibrosis" in Journal of Hepatology, 78, no. S1 (2023),
https://hdl.handle.net/21.15107/rcub_farfar_4912 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Ilić, Aleksandra
AU  - Čebzan, Alen
AU  - Radović, Branko
AU  - Ružić, Dušan
AU  - Đurić, Ana
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5001
AB  - Pancreatic ductal adenocarcinoma (PDAC) ranks among the most formidable and deadly
types of cancer. The emergence of chemoresistance in PDAC plays a significant role in the
unfavorable survival rates, making it imperative to swiftly develop new pharmaceutical
strategies to address this issue and improve treatment outcomes for PDAC (1). Considering
the numerous epigenetic changes observed in PDAC, the utilization of epigenetic drugs,
such as histone deacetylase (HDAC) inhibitors, holds a great promise as a transformative
approach, particularly when used in combination therapy settings (2).
In this study, we investigated the potential of utilizing drug sensitivity data and the basal
gene expression of pancreatic carcinoma cell lines to develop a bioinformatics screening
protocol for prediction of the combinatorial options available for HDAC inhibitors, including
sirtuin (SIRT) inhibitors. Experimental validation of the protocol performed on the two
pancreatic carcinoma cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified
synergisms between HDAC inhibitors and sphingosine 1-phosphate (S1P) receptor agonist
– fingolimod, or HDAC inhibitors and Rho-associated protein kinase (ROCK) inhibitor – RKI1447 (3).
Developed bioinformatics screening protocol for predictions of synergistic drug
combinations in PDAC identified several previously unreported interaction partners of
HDAC inhibitors. Predicted interaction partners of HDAC inhibitors including Aurora Kinase
A (AURKA) inhibitor, glutaminase (GLS) inhibitor and WEE1 kinase inhibitor were selected
for the design of novel classes of dual-acting HDAC inhibitors by the means of structure-based molecular modelling. Novel dual inhibitors (SIRT/AURKA, HDAC/GLS and HDAC/WEE1)
were designed relying on the known pharmacophoric features and molecular docking
models developed for each of the targets of interest. The docking scores of the designed
inhibitors revealed a notable affinity towards the specific targets. Additionally, when
combined with predictions of drug synergy, these designed molecules exhibit great
potential as promising structures for subsequent experimental evaluation.
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  - Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling
SP  - 47
EP  - 47
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5001
ER  - 

@conference{
author = "Đoković, Nemanja and Ilić, Aleksandra and Čebzan, Alen and Radović, Branko and Ružić, Dušan and Đurić, Ana and Srdić-Rajić, Tatjana and Nikolić, Katarina",
year = "2023",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) ranks among the most formidable and deadly
types of cancer. The emergence of chemoresistance in PDAC plays a significant role in the
unfavorable survival rates, making it imperative to swiftly develop new pharmaceutical
strategies to address this issue and improve treatment outcomes for PDAC (1). Considering
the numerous epigenetic changes observed in PDAC, the utilization of epigenetic drugs,
such as histone deacetylase (HDAC) inhibitors, holds a great promise as a transformative
approach, particularly when used in combination therapy settings (2).
In this study, we investigated the potential of utilizing drug sensitivity data and the basal
gene expression of pancreatic carcinoma cell lines to develop a bioinformatics screening
protocol for prediction of the combinatorial options available for HDAC inhibitors, including
sirtuin (SIRT) inhibitors. Experimental validation of the protocol performed on the two
pancreatic carcinoma cell lines (MIA PaCa-2 cells and PANC-1) confirmed the identified
synergisms between HDAC inhibitors and sphingosine 1-phosphate (S1P) receptor agonist
– fingolimod, or HDAC inhibitors and Rho-associated protein kinase (ROCK) inhibitor – RKI1447 (3).
Developed bioinformatics screening protocol for predictions of synergistic drug
combinations in PDAC identified several previously unreported interaction partners of
HDAC inhibitors. Predicted interaction partners of HDAC inhibitors including Aurora Kinase
A (AURKA) inhibitor, glutaminase (GLS) inhibitor and WEE1 kinase inhibitor were selected
for the design of novel classes of dual-acting HDAC inhibitors by the means of structure-based molecular modelling. Novel dual inhibitors (SIRT/AURKA, HDAC/GLS and HDAC/WEE1)
were designed relying on the known pharmacophoric features and molecular docking
models developed for each of the targets of interest. The docking scores of the designed
inhibitors revealed a notable affinity towards the specific targets. Additionally, when
combined with predictions of drug synergy, these designed molecules exhibit great
potential as promising structures for subsequent experimental evaluation.",
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 = "Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling",
pages = "47-47",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5001"
}

Đoković, N., Ilić, A., Čebzan, A., Radović, B., Ružić, D., Đurić, A., Srdić-Rajić, T.,& Nikolić, K.. (2023). Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling. 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., 47-47.
https://hdl.handle.net/21.15107/rcub_farfar_5001

Đoković N, Ilić A, Čebzan A, Radović B, Ružić D, Đurić A, Srdić-Rajić T, Nikolić K. Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling. 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;:47-47.
https://hdl.handle.net/21.15107/rcub_farfar_5001 .

Đoković, Nemanja, Ilić, Aleksandra, Čebzan, Alen, Radović, Branko, Ružić, Dušan, Đurić, Ana, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Towards the multitarget HDAC Inhibitors for the treatment of pancreatic carcinoma by joining the drug synergy predictions and the molecular modeling" 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):47-47,
https://hdl.handle.net/21.15107/rcub_farfar_5001 .

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  - CONF
AU  - Čebzan, Alen
AU  - Ružić, Dušan
AU  - Nikolić, Katarina
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4952
PB  - European Association for Cancer Research
C3  - EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023
T1  - Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4952
ER  - 

@conference{
author = "Čebzan, Alen and Ružić, Dušan and Nikolić, Katarina",
year = "2023",
publisher = "European Association for Cancer Research",
journal = "EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023",
title = "Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4952"
}

Čebzan, A., Ružić, D.,& Nikolić, K.. (2023). Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking. in EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023
European Association for Cancer Research..
https://hdl.handle.net/21.15107/rcub_farfar_4952

Čebzan A, Ružić D, Nikolić K. Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking. in EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_4952 .

Čebzan, Alen, Ružić, Dušan, Nikolić, Katarina, "Computer-aided drug design of MAPK inhibitors by combined 3D-QSAR analysis and molecular docking" in EACR-Boehringer Ingelheim Drugging and Regulating the MAP Kinase Pathway Virtual Event, Worldwide : 21 - 22 February 2023 (2023),
https://hdl.handle.net/21.15107/rcub_farfar_4952 .

TY  - CONF
AU  - Sánchez-Martín, Victoria
AU  - Ružić, Dušan
AU  - Castilla-Maldonado, Ignacio
AU  - Ortiz-González, Matilde
AU  - Soriano-Lerma, Ana
AU  - Linde-Rodríguez, Ángel
AU  - Pérez-Carrasco, Virginia
AU  - Ramirez-Macias, Inmaculada
AU  - Soriano, Miguel
AU  - Nikolić, Katarina
AU  - García-Salcedo, Jose Antonio
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4911
AB  - Metastasis is a major problem in the management of cancer, remaining as the principal cause of cancer death. Despite recent advances, treatment options are still limited. Naphthalimide (1H-benzo[de]isoquinoline-1,3-(2H)-dione) analogs have been considered as promising anticancer agents against different tumor types. However, antimetastatic potential of naphthalimides has not been previously established. The aim of this work was to evaluate the possible antimetastatic activ-ity of a panel of 21 naphthalimides which were synthesized in the laboratory. We studied the inhib-itory effects of these compounds on cancer proliferation, clonogenicity and cell cycle progression. We identified 5 naphthalimides with a potent and selective inhibition of growth in SW620 metastatic cells compared to CRL1790 non-tumoral ones. In addition, these 5 naphthalimides induced a sig-nificant arrest at S and G2/M phase in SW620 cells. Finally, we selected the leading compound 20B, which inhibited clonogenic expansion in SW620 cells even at 10 μM. These results shed light on 20B naphthalimide as an emerging antimetastatic agent. Future studies are required to determine its mechanism of action.
PB  - MDPI
C3  - Medical sciences forum
T1  - Screening of naphthalimides as antimetastatic agents
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4911
ER  - 

@conference{
author = "Sánchez-Martín, Victoria and Ružić, Dušan and Castilla-Maldonado, Ignacio and Ortiz-González, Matilde and Soriano-Lerma, Ana and Linde-Rodríguez, Ángel and Pérez-Carrasco, Virginia and Ramirez-Macias, Inmaculada and Soriano, Miguel and Nikolić, Katarina and García-Salcedo, Jose Antonio",
year = "2023",
abstract = "Metastasis is a major problem in the management of cancer, remaining as the principal cause of cancer death. Despite recent advances, treatment options are still limited. Naphthalimide (1H-benzo[de]isoquinoline-1,3-(2H)-dione) analogs have been considered as promising anticancer agents against different tumor types. However, antimetastatic potential of naphthalimides has not been previously established. The aim of this work was to evaluate the possible antimetastatic activ-ity of a panel of 21 naphthalimides which were synthesized in the laboratory. We studied the inhib-itory effects of these compounds on cancer proliferation, clonogenicity and cell cycle progression. We identified 5 naphthalimides with a potent and selective inhibition of growth in SW620 metastatic cells compared to CRL1790 non-tumoral ones. In addition, these 5 naphthalimides induced a sig-nificant arrest at S and G2/M phase in SW620 cells. Finally, we selected the leading compound 20B, which inhibited clonogenic expansion in SW620 cells even at 10 μM. These results shed light on 20B naphthalimide as an emerging antimetastatic agent. Future studies are required to determine its mechanism of action.",
publisher = "MDPI",
journal = "Medical sciences forum",
title = "Screening of naphthalimides as antimetastatic agents",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4911"
}

Sánchez-Martín, V., Ružić, D., Castilla-Maldonado, I., Ortiz-González, M., Soriano-Lerma, A., Linde-Rodríguez, Á., Pérez-Carrasco, V., Ramirez-Macias, I., Soriano, M., Nikolić, K.,& García-Salcedo, J. A.. (2023). Screening of naphthalimides as antimetastatic agents. in Medical sciences forum
MDPI..
https://hdl.handle.net/21.15107/rcub_farfar_4911

Sánchez-Martín V, Ružić D, Castilla-Maldonado I, Ortiz-González M, Soriano-Lerma A, Linde-Rodríguez Á, Pérez-Carrasco V, Ramirez-Macias I, Soriano M, Nikolić K, García-Salcedo JA. Screening of naphthalimides as antimetastatic agents. in Medical sciences forum. 2023;.
https://hdl.handle.net/21.15107/rcub_farfar_4911 .

Sánchez-Martín, Victoria, Ružić, Dušan, Castilla-Maldonado, Ignacio, Ortiz-González, Matilde, Soriano-Lerma, Ana, Linde-Rodríguez, Ángel, Pérez-Carrasco, Virginia, Ramirez-Macias, Inmaculada, Soriano, Miguel, Nikolić, Katarina, García-Salcedo, Jose Antonio, "Screening of naphthalimides as antimetastatic agents" in Medical sciences forum (2023),
https://hdl.handle.net/21.15107/rcub_farfar_4911 .

TY  - CONF
AU  - Bošković, Jelena
AU  - Dobričić, Vladimir
AU  - Ružić, Dušan
AU  - Nikolić, Katarina
AU  - Čudina, Olivera
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5451
AB  - Inflammation is a part of immune system's response to harmful intrinsic and
extrinsic stimuli, such as infection or injury. It has an important role in progression of some diseases, such as cancer, arthritis, stroke [1]. It is considered that inhibition of COX 2 and 5 LOX pathways of production of inflammation mediators provides a new strategy for development of more effective anticancer drugs [2]. The aim of this study was designing of novel COX 2/5 LOX inhibitors with improved activity towards both enzymes using quantitative structure activity relationships (QSAR). QSAR modeling was applied on a literature data set consisting of 28 dual COX 2/5 LOX inhibitors and obtained pharmacophoric features were used in design of novel compounds. Regarding prediction of activity of novel COX 2 and 5 LOX inhibitors, two models were developed. Based on values of Q2 (0.53 (COX 2 model) and 0.71 (5 LOX model)) and R2 pred (0.85 (for both COX 2 and 5 LOX models)), developed models have good predictive ability and can be used for activity prediction of novel designed compounds.
Obtained values of r2m, r'2m, and r ̅2m were higher than 0.5 and Δr2m was lower than 0.2 indicating high predictive quality of developed models. Applicability domain (AD) was defined using Leverage approach and all compounds were inside the AD. In order to get more potent dual inhibitors of COX 2 and 5 LOX enzymes, compounds with high pIC50 values were chosen for design of novel compounds. As a result, 32 novel compounds were designed and according to predicted pIC50 values can be considered promising dual COX 2 and 5 LOX inhibitors.
PB  - Institut Químic de Sarrià - Universitat Ramon Llull (IQS-URL)
C3  - MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts
T1  - Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis
SP  - 57
EP  - 57
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5451
ER  - 

@conference{
author = "Bošković, Jelena and Dobričić, Vladimir and Ružić, Dušan and Nikolić, Katarina and Čudina, Olivera",
year = "2022",
abstract = "Inflammation is a part of immune system's response to harmful intrinsic and
extrinsic stimuli, such as infection or injury. It has an important role in progression of some diseases, such as cancer, arthritis, stroke [1]. It is considered that inhibition of COX 2 and 5 LOX pathways of production of inflammation mediators provides a new strategy for development of more effective anticancer drugs [2]. The aim of this study was designing of novel COX 2/5 LOX inhibitors with improved activity towards both enzymes using quantitative structure activity relationships (QSAR). QSAR modeling was applied on a literature data set consisting of 28 dual COX 2/5 LOX inhibitors and obtained pharmacophoric features were used in design of novel compounds. Regarding prediction of activity of novel COX 2 and 5 LOX inhibitors, two models were developed. Based on values of Q2 (0.53 (COX 2 model) and 0.71 (5 LOX model)) and R2 pred (0.85 (for both COX 2 and 5 LOX models)), developed models have good predictive ability and can be used for activity prediction of novel designed compounds.
Obtained values of r2m, r'2m, and r ̅2m were higher than 0.5 and Δr2m was lower than 0.2 indicating high predictive quality of developed models. Applicability domain (AD) was defined using Leverage approach and all compounds were inside the AD. In order to get more potent dual inhibitors of COX 2 and 5 LOX enzymes, compounds with high pIC50 values were chosen for design of novel compounds. As a result, 32 novel compounds were designed and according to predicted pIC50 values can be considered promising dual COX 2 and 5 LOX inhibitors.",
publisher = "Institut Químic de Sarrià - Universitat Ramon Llull (IQS-URL)",
journal = "MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts",
title = "Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis",
pages = "57-57",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5451"
}

Bošković, J., Dobričić, V., Ružić, D., Nikolić, K.,& Čudina, O.. (2022). Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis. in MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts
Institut Químic de Sarrià - Universitat Ramon Llull (IQS-URL)., 57-57.
https://hdl.handle.net/21.15107/rcub_farfar_5451

Bošković J, Dobričić V, Ružić D, Nikolić K, Čudina O. Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis. in MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts. 2022;:57-57.
https://hdl.handle.net/21.15107/rcub_farfar_5451 .

Bošković, Jelena, Dobričić, Vladimir, Ružić, Dušan, Nikolić, Katarina, Čudina, Olivera, "Design of novel dual COX 2 and 5 LOX inhibitors using quantitative structure activity relationships analysis" in MedChem 2022, XI Paul Ehrlich Euro-PhD Network, Barcelona, July 14th - 16th 2022, Book of Abstracts (2022):57-57,
https://hdl.handle.net/21.15107/rcub_farfar_5451 .

TY  - JOUR
AU  - Bošković, Jelena
AU  - Ružić, Dušan
AU  - Čudina, Olivera
AU  - Nikolić, Katarina
AU  - Dobričić, Vladimir
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5442
AB  - Background: Inflammation is a critical component of many disease progressions, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of inflammatory mediators synthesis by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides challenging strategy for development of more effective drugs.

Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods..

Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5- LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software.

Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, were clustered as potential dual COX-2 and 5-LOX inhibitors with ironchelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had ADMET_Risk score less than 7 and CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946).

Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g and 1l) were selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.
PB  - Bentham Science Publishers
T2  - Letters in Drug Design & Discovery
T1  - Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods
VL  - 19
IS  - 4
SP  - 279
EP  - 292
DO  - 10.2174/1570180818666210714161908
ER  - 

@article{
author = "Bošković, Jelena and Ružić, Dušan and Čudina, Olivera and Nikolić, Katarina and Dobričić, Vladimir",
year = "2022",
abstract = "Background: Inflammation is a critical component of many disease progressions, such as malignancy, cardiovascular and rheumatic diseases. The inhibition of inflammatory mediators synthesis by modulation of cyclooxygenase (COX) and lipoxygenase (LOX) pathways provides challenging strategy for development of more effective drugs.

Objective: The aim of this study was to design dual COX-2 and 5-LOX inhibitors with iron-chelating properties using a combination of ligand-based (three-dimensional quantitative structure-activity relationship (3D-QSAR)) and structure-based (molecular docking) methods..

Methods: The 3D-QSAR analysis was applied on a literature dataset consisting of 28 dual COX-2 and 5- LOX inhibitors in Pentacle software. The quality of developed COX-2 and 5-LOX 3D-QSAR models were evaluated by internal and external validation methods. The molecular docking analysis was performed in GOLD software, while selected ADMET properties were predicted in ADMET predictor software.

Results: According to the molecular docking studies, the class of sulfohydroxamic acid analogues, previously designed by 3D-QSAR, were clustered as potential dual COX-2 and 5-LOX inhibitors with ironchelating properties. Based on the 3D-QSAR and molecular docking, 1j, 1g and 1l were selected as the most promising dual COX-2 and 5-LOX inhibitors. According to the in silico ADMET predictions, all compounds had ADMET_Risk score less than 7 and CYP_Risk score lower than 2.5. Designed compounds were not estimated as hERG inhibitors and 1j had improved intrinsic solubility (8.704) in comparison to the dataset compounds (0.411-7.946).

Conclusion: By combining 3D-QSAR and molecular docking, three compounds (1j, 1g and 1l) were selected as the most promising designed dual COX-2 and 5-LOX inhibitors, for which good activity, as well as favourable ADMET properties and toxicity, are expected.",
publisher = "Bentham Science Publishers",
journal = "Letters in Drug Design & Discovery",
title = "Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods",
volume = "19",
number = "4",
pages = "279-292",
doi = "10.2174/1570180818666210714161908"
}

Bošković, J., Ružić, D., Čudina, O., Nikolić, K.,& Dobričić, V.. (2022). Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods. in Letters in Drug Design & Discovery
Bentham Science Publishers., 19(4), 279-292.
https://doi.org/10.2174/1570180818666210714161908

Bošković J, Ružić D, Čudina O, Nikolić K, Dobričić V. Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods. in Letters in Drug Design & Discovery. 2022;19(4):279-292.
doi:10.2174/1570180818666210714161908 .

Bošković, Jelena, Ružić, Dušan, Čudina, Olivera, Nikolić, Katarina, Dobričić, Vladimir, "Design of Dual COX-2 and 5-LOX Inhibitors with Iron-Chelating Properties Using Structure-Based and Ligand-Based Methods" in Letters in Drug Design & Discovery, 19, no. 4 (2022):279-292,
https://doi.org/10.2174/1570180818666210714161908 . .

TY  - GEN
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/123456789/5462
AB  - Intricate structural heterogeneity of SIRT2
Initial goal: Discovery of novel scaffolds of SIRT2
inhibitors.
Experimentally confirmed conformal flexibility of SIRT2
binding site place it in the group of structures of
relatively challenging targets for modeling.
Different chemistry = Different conformational state
Scientific question: Have we discovered all states of
SIRT2?
Why deciphering of binding pocket dynamics is that
important from the aspect of structure-based drug
design?
T2  - Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022
T1  - Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5462
ER  - 

@misc{
author = "Đoković, Nemanja and Ružić, Dušan and Rahnasto‐Rilla, Minna and Srdić Rajić, Tatjana and Lahtela-Kakkonen, Maija and Nikolić, Katarina",
year = "2022",
abstract = "Intricate structural heterogeneity of SIRT2
Initial goal: Discovery of novel scaffolds of SIRT2
inhibitors.
Experimentally confirmed conformal flexibility of SIRT2
binding site place it in the group of structures of
relatively challenging targets for modeling.
Different chemistry = Different conformational state
Scientific question: Have we discovered all states of
SIRT2?
Why deciphering of binding pocket dynamics is that
important from the aspect of structure-based drug
design?",
journal = "Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022",
title = "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5462"
}

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 Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022.
https://hdl.handle.net/21.15107/rcub_farfar_5462

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 Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_5462 .

Đoković, Nemanja, Ružić, Dušan, Rahnasto‐Rilla, Minna, Srdić Rajić, Tatjana, Lahtela-Kakkonen, Maija, Nikolić, Katarina, "Expanding the Accessible Chemical Space of SIRT2 Inhibitors through Exploration of Binding Pocket Dynamics" in Scientific Modeling Studies Serie, University of Eastern Finland, Kuopio, Finland, 16 May 2022 (2022),
https://hdl.handle.net/21.15107/rcub_farfar_5462 .

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 . .

TY  - THES
AU  - Ružić, Dušan
PY  - 2022
UR  - https://eteze.bg.ac.rs/application/showtheses?thesesId=9074
UR  - https://fedorabg.bg.ac.rs/fedora/get/o:29265/bdef:Content/download
UR  - https://plus.cobiss.net/cobiss/sr/sr/bib/70819081
UR  - https://nardus.mpn.gov.rs/handle/123456789/21425
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4849
AB  - Histon deacetilaze su metaloenzimi koji hidrolizuju acetilovane bočne amino grupe lizina nahistonskim i nehistonskim proteinima. Uklanjanjem acetil grupe sa lizina generiše se pozitivnonaelektrisanje na histonima, koje gradi jonske veze sa negativno naelektrisanim DNK molekulima.Kao posledica građenja jonskih veza, hromatin postaje gusto pakovan, teže dostupantranskripcionim faktorima, koji posledično dovodi do represije genske transkripcije. Uepigenetičkim istraživanjima, derivati hidroksamskih kiselina se koriste u dizajniranju inhibitorahiston deacetilaza. Posledica inhibicije histon deacetilaza je indukcija apoptoze, zastoj u ćelijskomciklusu, smanjenje rasta tumora, inhibicija migracije i invazije malignih ćelija. U zavisnosti odhomologije u primarnoj sekvenci i ćelijske lokalizacije, histon deacetilaze su podeljene u četiriklase. Klasi I pripadaju HDAC1, HDAC2, HDAC3 i HDAC8 izoforme. Klasa II se deli na dvepodklase – klasu IIa (HDAC4, HDAC5, HDAC7 i HDAC9), dok klasi IIb pripadaju HDAC6 iHDAC10. Posebno se izdvaja izoforma HDAC11 u okviru klase IV humanih histon deacetilaza.Prva faza istraživanja u ovoj doktorskoj disertaciji je kompjutersko dizajniranje selektivnihinhibitora histon deacetilaze 6. Dizajniranje pomenutih inhibitora je omogućeno kombinovanjemstudija kvantitativnog odnosa strukture i aktivnosti (3D-QSAR), pretrage novih fragmenata, kao istudija molekulskog dokinga na trodimenzionalnim strukturama histon deacetilaza 1 i 6. Druga fazaistraživanja bila je sinteza odabranih jedinjenja na osnovu zaključaka in silico studija racionalnogdizajna selektivnih HDAC6 inhibitora. Treća faza istraživanja u ovoj doktorskoj disertaciji jeodređivanje vrednosti inhibitornih koncentracija (IC50) novosintetisanih jedinjenja na humanimHDAC1, HDAC3, HDAC6 i HDAC8 izoenzimima u in vitro enzimskim testovima. Ispitivanjeantikancerskih osobina sintetisanih jedinjenja na ćelijama tumora dojke (MDA-MB-231 i MCF-7)predstavlja četvrtu fazu istraživanja u ovoj doktorskoj disertaciji.Kao rezultat kompjuterskog dizajniranja selektivnih inhibitora histon deacetilaze 6 izdvojeni sevalidni i prediktivni 3D-QSAR modeli. Tehnikom virtuelnog skrininga odabrani su odgovarajućifragmenti za dizajniranje selektivnih HDAC6 inhibitora. Molekulskim dokingom je predviđen načinvezivanja dizajniranih jedinjenja za humane HDAC1 i HDAC6 izoforme. Sintetisane su dve klasederivata hidroksamskih kiselina, derivati 1-benzhidrilnog piperazina i klasa 5,5-difenil-2,4-imidazolidindiona i okarakterisani metodama strukturne analize. Na osnovu rezultata in vitroenzimskih testiranja, identifikovano je sedam nanomolarnih inhibitora histon deacetilaze 6, od kojihsu dva inhibitora: BDR-6, IC50 = 186 nM i BDR-9, IC50 = 31 nM selektivna za HDAC6 izoformu ijedan inhibitor je izdvojen kao dualni HDAC6/8 inhibitor. Ispitivanjima uticaja sintetisanih inhibitorana ćelijsko preživljavanje, apoptozu, promene u ćelijskom ciklusu, migraciju i invaziju ćelija kanceradojke (MDA-MB-231 i MCF-7) izdvojen je neselektivni HDAC inhibitor, BDR-8 (HDAC1, IC50 =408 nM; HDAC3 IC50 = 207 nM; HDAC6, IC50 = 124 nM i HDAC8, IC50 = 245 nM) sa najboljimantikancerskim osobinama. Najpotentniji sintetisani selektivni HDAC6 inhibitor, BDR-9 predstavljanecitotoksično jedinjenje sa antimigratornim osobinama na MCF-7 ćelijama kancera dojke. U ovojdoktorskoj disertaciji prikazan je sistematičan protokol za preklinički razvoj novih selektivnihinhibitora histon deacetilaze 6, koji može da bude iskorišćen u budućim istraživanjima u oblastiotkrića lekova koji deluju na kancerski epigenom.
AB  - Histone deacetylases are metalloenzymes that hydrolyze acetylated lysine side chains on histoneand non-histone proteins. Removal of the acetyl group from lysine generates a positive charge onhistones that forms ionic bonds with negatively charged DNA molecules. As a consequence offorming ionic bonds, chromatin becomes densely packed, the access of the transcription factors isprevented, which in turn leads to the repression of gene transcription. In epigenetic drugdiscovery, hydroxamic acid derivatives are used in the design of histone deacetylase inhibitors.Inhibition of human histone deacetylases leads to induction of apoptosis, cell cycle arrest, tumorgrowth inhibition, inhibition of migration and invasion of malignant cells. Depending on thehomology in the primary sequence and cell localization, histone deacetylases are classified intofour classes. Class I is consisted of HDAC1, HDAC2, HDAC3 and HDAC8 isoforms. Class II isdivided into two subclasses - class IIa (HDAC4, HDAC5, HDAC7 and HDAC9), and class IIb(HDAC6 and HDAC10). The HDAC11 is the unique isoform within the class IV HDACs.The first goal of research in this doctoral dissertation was computational drug design of selectivehistone deacetylase 6 inhibitors. The second goal of the research was the synthesis of selectedcompounds based on the predictions of in silico studies. The third research goal in this doctoraldissertation is to determine the inhibitory concentrations (IC50) of newly synthesized compoundsagainst human HDAC1, HDAC3, HDAC6 and HDAC8 isoenzymes in in vitro enzyme assays.Evaluation of anticancer properties of synthesized compounds on breast tumor cells (MDA-MB-231 and MCF-7) is the fourth goal set in this doctoral dissertation.As a result of computational drug design study, valid and predictive 3D-QSAR models weregenerated. The most promising fragments for the design of selective HDAC6 inhibitors wereselected by virtual screening technique. Molecular docking study predicted the binding modes ofdesigned compounds toward the human HDAC1 and HDAC6 isoforms. Two classes ofhydroxamic acid derivatives, 1-benzhydryl piperazine derivatives and 5,5-diphenyl-imidazolidine-2,4-dione derivatives were synthesized and characterized by NMR analysis and mass spectrometry.Considering the results of in vitro enzyme assays, seven nanomolar histone deacetylase 6 inhibitorswere identified, of which two inhibitors: BDR-6, IC50 = 186 nM and BDR-9, IC50 = 31 nM areselective for HDAC6 isoform and one inhibitor was disclosed as dual HDAC6 / 8 inhibitor.Evaluation of the effects of synthesized inhibitors on cell survival, apoptosis, changes in cell cycle,migration and invasion of breast cancer cells (MDA-MB-231 and MCF-7) singled out a non-selective HDAC inhibitor, BDR-8 (HDAC1, IC50 = 408 nM; HDAC3 IC50 = 207 nM, HDAC6, IC50= 124 nM and HDAC8, IC50 = 245 nM) with the best anticancer properties. The most potentselective HDAC6 inhibitor, BDR-9 is a non-cytotoxic compound with anti-migratory properties onMCF-7 breast cancer cells. In this doctoral dissertation, a systematic protocol for the preclinicaldrug discovery of novel selective histone deacetylase 6 inhibitors is presented, that can be used infuture research of drug candidates that target the cancer epigenome.
PB  - Универзитет у Београду, Фармацеутски факултет
T2  - Универзитет у Београду
T1  - Racionalni dizajn, sinteza i in vitro ispitivanja selektivnih inhibitora histon deacetilaze 6
UR  - https://hdl.handle.net/21.15107/rcub_nardus_21425
ER  - 

@phdthesis{
author = "Ružić, Dušan",
year = "2022",
abstract = "Histon deacetilaze su metaloenzimi koji hidrolizuju acetilovane bočne amino grupe lizina nahistonskim i nehistonskim proteinima. Uklanjanjem acetil grupe sa lizina generiše se pozitivnonaelektrisanje na histonima, koje gradi jonske veze sa negativno naelektrisanim DNK molekulima.Kao posledica građenja jonskih veza, hromatin postaje gusto pakovan, teže dostupantranskripcionim faktorima, koji posledično dovodi do represije genske transkripcije. Uepigenetičkim istraživanjima, derivati hidroksamskih kiselina se koriste u dizajniranju inhibitorahiston deacetilaza. Posledica inhibicije histon deacetilaza je indukcija apoptoze, zastoj u ćelijskomciklusu, smanjenje rasta tumora, inhibicija migracije i invazije malignih ćelija. U zavisnosti odhomologije u primarnoj sekvenci i ćelijske lokalizacije, histon deacetilaze su podeljene u četiriklase. Klasi I pripadaju HDAC1, HDAC2, HDAC3 i HDAC8 izoforme. Klasa II se deli na dvepodklase – klasu IIa (HDAC4, HDAC5, HDAC7 i HDAC9), dok klasi IIb pripadaju HDAC6 iHDAC10. Posebno se izdvaja izoforma HDAC11 u okviru klase IV humanih histon deacetilaza.Prva faza istraživanja u ovoj doktorskoj disertaciji je kompjutersko dizajniranje selektivnihinhibitora histon deacetilaze 6. Dizajniranje pomenutih inhibitora je omogućeno kombinovanjemstudija kvantitativnog odnosa strukture i aktivnosti (3D-QSAR), pretrage novih fragmenata, kao istudija molekulskog dokinga na trodimenzionalnim strukturama histon deacetilaza 1 i 6. Druga fazaistraživanja bila je sinteza odabranih jedinjenja na osnovu zaključaka in silico studija racionalnogdizajna selektivnih HDAC6 inhibitora. Treća faza istraživanja u ovoj doktorskoj disertaciji jeodređivanje vrednosti inhibitornih koncentracija (IC50) novosintetisanih jedinjenja na humanimHDAC1, HDAC3, HDAC6 i HDAC8 izoenzimima u in vitro enzimskim testovima. Ispitivanjeantikancerskih osobina sintetisanih jedinjenja na ćelijama tumora dojke (MDA-MB-231 i MCF-7)predstavlja četvrtu fazu istraživanja u ovoj doktorskoj disertaciji.Kao rezultat kompjuterskog dizajniranja selektivnih inhibitora histon deacetilaze 6 izdvojeni sevalidni i prediktivni 3D-QSAR modeli. Tehnikom virtuelnog skrininga odabrani su odgovarajućifragmenti za dizajniranje selektivnih HDAC6 inhibitora. Molekulskim dokingom je predviđen načinvezivanja dizajniranih jedinjenja za humane HDAC1 i HDAC6 izoforme. Sintetisane su dve klasederivata hidroksamskih kiselina, derivati 1-benzhidrilnog piperazina i klasa 5,5-difenil-2,4-imidazolidindiona i okarakterisani metodama strukturne analize. Na osnovu rezultata in vitroenzimskih testiranja, identifikovano je sedam nanomolarnih inhibitora histon deacetilaze 6, od kojihsu dva inhibitora: BDR-6, IC50 = 186 nM i BDR-9, IC50 = 31 nM selektivna za HDAC6 izoformu ijedan inhibitor je izdvojen kao dualni HDAC6/8 inhibitor. Ispitivanjima uticaja sintetisanih inhibitorana ćelijsko preživljavanje, apoptozu, promene u ćelijskom ciklusu, migraciju i invaziju ćelija kanceradojke (MDA-MB-231 i MCF-7) izdvojen je neselektivni HDAC inhibitor, BDR-8 (HDAC1, IC50 =408 nM; HDAC3 IC50 = 207 nM; HDAC6, IC50 = 124 nM i HDAC8, IC50 = 245 nM) sa najboljimantikancerskim osobinama. Najpotentniji sintetisani selektivni HDAC6 inhibitor, BDR-9 predstavljanecitotoksično jedinjenje sa antimigratornim osobinama na MCF-7 ćelijama kancera dojke. U ovojdoktorskoj disertaciji prikazan je sistematičan protokol za preklinički razvoj novih selektivnihinhibitora histon deacetilaze 6, koji može da bude iskorišćen u budućim istraživanjima u oblastiotkrića lekova koji deluju na kancerski epigenom., Histone deacetylases are metalloenzymes that hydrolyze acetylated lysine side chains on histoneand non-histone proteins. Removal of the acetyl group from lysine generates a positive charge onhistones that forms ionic bonds with negatively charged DNA molecules. As a consequence offorming ionic bonds, chromatin becomes densely packed, the access of the transcription factors isprevented, which in turn leads to the repression of gene transcription. In epigenetic drugdiscovery, hydroxamic acid derivatives are used in the design of histone deacetylase inhibitors.Inhibition of human histone deacetylases leads to induction of apoptosis, cell cycle arrest, tumorgrowth inhibition, inhibition of migration and invasion of malignant cells. Depending on thehomology in the primary sequence and cell localization, histone deacetylases are classified intofour classes. Class I is consisted of HDAC1, HDAC2, HDAC3 and HDAC8 isoforms. Class II isdivided into two subclasses - class IIa (HDAC4, HDAC5, HDAC7 and HDAC9), and class IIb(HDAC6 and HDAC10). The HDAC11 is the unique isoform within the class IV HDACs.The first goal of research in this doctoral dissertation was computational drug design of selectivehistone deacetylase 6 inhibitors. The second goal of the research was the synthesis of selectedcompounds based on the predictions of in silico studies. The third research goal in this doctoraldissertation is to determine the inhibitory concentrations (IC50) of newly synthesized compoundsagainst human HDAC1, HDAC3, HDAC6 and HDAC8 isoenzymes in in vitro enzyme assays.Evaluation of anticancer properties of synthesized compounds on breast tumor cells (MDA-MB-231 and MCF-7) is the fourth goal set in this doctoral dissertation.As a result of computational drug design study, valid and predictive 3D-QSAR models weregenerated. The most promising fragments for the design of selective HDAC6 inhibitors wereselected by virtual screening technique. Molecular docking study predicted the binding modes ofdesigned compounds toward the human HDAC1 and HDAC6 isoforms. Two classes ofhydroxamic acid derivatives, 1-benzhydryl piperazine derivatives and 5,5-diphenyl-imidazolidine-2,4-dione derivatives were synthesized and characterized by NMR analysis and mass spectrometry.Considering the results of in vitro enzyme assays, seven nanomolar histone deacetylase 6 inhibitorswere identified, of which two inhibitors: BDR-6, IC50 = 186 nM and BDR-9, IC50 = 31 nM areselective for HDAC6 isoform and one inhibitor was disclosed as dual HDAC6 / 8 inhibitor.Evaluation of the effects of synthesized inhibitors on cell survival, apoptosis, changes in cell cycle,migration and invasion of breast cancer cells (MDA-MB-231 and MCF-7) singled out a non-selective HDAC inhibitor, BDR-8 (HDAC1, IC50 = 408 nM; HDAC3 IC50 = 207 nM, HDAC6, IC50= 124 nM and HDAC8, IC50 = 245 nM) with the best anticancer properties. The most potentselective HDAC6 inhibitor, BDR-9 is a non-cytotoxic compound with anti-migratory properties onMCF-7 breast cancer cells. In this doctoral dissertation, a systematic protocol for the preclinicaldrug discovery of novel selective histone deacetylase 6 inhibitors is presented, that can be used infuture research of drug candidates that target the cancer epigenome.",
publisher = "Универзитет у Београду, Фармацеутски факултет",
journal = "Универзитет у Београду",
title = "Racionalni dizajn, sinteza i in vitro ispitivanja selektivnih inhibitora histon deacetilaze 6",
url = "https://hdl.handle.net/21.15107/rcub_nardus_21425"
}

Ružić, D.. (2022). Racionalni dizajn, sinteza i in vitro ispitivanja selektivnih inhibitora histon deacetilaze 6. in Универзитет у Београду
Универзитет у Београду, Фармацеутски факултет..
https://hdl.handle.net/21.15107/rcub_nardus_21425

Ružić D. Racionalni dizajn, sinteza i in vitro ispitivanja selektivnih inhibitora histon deacetilaze 6. in Универзитет у Београду. 2022;.
https://hdl.handle.net/21.15107/rcub_nardus_21425 .

Ružić, Dušan, "Racionalni dizajn, sinteza i in vitro ispitivanja selektivnih inhibitora histon deacetilaze 6" in Универзитет у Београду (2022),
https://hdl.handle.net/21.15107/rcub_nardus_21425 .

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  - 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  - 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  - GEN
AU  - Ružić, Dušan
AU  - Ellinger, Bernhard
AU  - Đoković, Nemanja
AU  - Santibanez, Juan
AU  - Ganesan, A.
AU  - Pavić, Aleksandar
AU  - Srdić Rajić, Tatjana
AU  - Petković, Miloš
AU  - Nikolić, Katarina
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4951
PB  - Institute Pasteur, France
T2  - Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022
T1  - Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4951
ER  - 

@misc{
author = "Ružić, Dušan and Ellinger, Bernhard and Đoković, Nemanja and Santibanez, Juan and Ganesan, A. and Pavić, Aleksandar and Srdić Rajić, Tatjana and Petković, Miloš and Nikolić, Katarina",
year = "2022",
publisher = "Institute Pasteur, France",
journal = "Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022",
title = "Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4951"
}

Ružić, D., Ellinger, B., Đoković, N., Santibanez, J., Ganesan, A., Pavić, A., Srdić Rajić, T., Petković, M.,& Nikolić, K.. (2022). Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy. in Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022
Institute Pasteur, France..
https://hdl.handle.net/21.15107/rcub_farfar_4951

Ružić D, Ellinger B, Đoković N, Santibanez J, Ganesan A, Pavić A, Srdić Rajić T, Petković M, Nikolić K. Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy. in Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022. 2022;.
https://hdl.handle.net/21.15107/rcub_farfar_4951 .

Ružić, Dušan, Ellinger, Bernhard, Đoković, Nemanja, Santibanez, Juan, Ganesan, A., Pavić, Aleksandar, Srdić Rajić, Tatjana, Petković, Miloš, Nikolić, Katarina, "Identification of novel 1-benzhydryl-piperazine derivatives as Histone Deacetylase inhibitors using Fragment-based drug design strategy" in Journal Club on Drug Design, Institute Pasteur, Paris, France November 25 2022 (2022),
https://hdl.handle.net/21.15107/rcub_farfar_4951 .

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., 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;: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 (2022):125-125,
https://hdl.handle.net/21.15107/rcub_farfar_4739 .

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  - JOUR
AU  - Bon, Corentin
AU  - Barbachowska, Magdalena
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Si, Yang
AU  - Soresinetti, Laura
AU  - Jallet, Corinne
AU  - Tafit, Ambre
AU  - Halby, Ludovic
AU  - Nikolić, Katarina
AU  - Arimondo, Paola B
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4908
AB  - Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors.
PB  - Newlands Press
T2  - Future Medicinal Chemistry
T1  - Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies
VL  - 14
VL  - 557
VL  - 570
IS  - 8
DO  - 10.4155/fmc-2021-0251
ER  - 

@article{
author = "Bon, Corentin and Barbachowska, Magdalena and Đoković, Nemanja and Ružić, Dušan and Si, Yang and Soresinetti, Laura and Jallet, Corinne and Tafit, Ambre and Halby, Ludovic and Nikolić, Katarina and Arimondo, Paola B",
year = "2022",
abstract = "Post-translational modifications of histones constitute a dynamic process impacting gene expression. A well-studied modification is lysine methylation. Among the lysine histone methyltransferases, DOT1L is implicated in various diseases, making it a very interesting target for drug discovery. DOT1L has two substrates, the SAM cofactor that gives the methyl group and the lysine H3K79 substrate. Results: Using molecular docking, the authors explored new bisubstrate analogs to enlarge the chemical landscape of DOT1L inhibitors. The authors showed that quinazoline can successfully replace the adenine in the design of bisubstrate inhibitors of DOT1L, showing similar activity compared with the adenine derivative but with diminished cytotoxicity. Conclusion: The docking model is validated together with the use of quinazoline in the design of bisubstrate inhibitors.",
publisher = "Newlands Press",
journal = "Future Medicinal Chemistry",
title = "Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies",
volume = "14, 557, 570",
number = "8",
doi = "10.4155/fmc-2021-0251"
}

Bon, C., Barbachowska, M., Đoković, N., Ružić, D., Si, Y., Soresinetti, L., Jallet, C., Tafit, A., Halby, L., Nikolić, K.,& Arimondo, P. B.. (2022). Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies. in Future Medicinal Chemistry
Newlands Press., 14(8).
https://doi.org/10.4155/fmc-2021-0251

Bon C, Barbachowska M, Đoković N, Ružić D, Si Y, Soresinetti L, Jallet C, Tafit A, Halby L, Nikolić K, Arimondo PB. Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies. in Future Medicinal Chemistry. 2022;14(8).
doi:10.4155/fmc-2021-0251 .

Bon, Corentin, Barbachowska, Magdalena, Đoković, Nemanja, Ružić, Dušan, Si, Yang, Soresinetti, Laura, Jallet, Corinne, Tafit, Ambre, Halby, Ludovic, Nikolić, Katarina, Arimondo, Paola B, "Quinazoline-based analog of adenine as an antidote against MLL-rearranged leukemia cells: synthesis, inhibition assays and docking studies" in Future Medicinal Chemistry, 14, no. 8 (2022),
https://doi.org/10.4155/fmc-2021-0251 . .

TY  - JOUR
AU  - Albert, Lea
AU  - Nagpal, Jatin
AU  - Steinchen, Wieland
AU  - Zhang, Lei
AU  - Werel, Laura
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Hoffarth, Malte
AU  - Xu, Jing
AU  - Kaspareit, Johanna
AU  - Abendroth, Frank
AU  - Royant, Antoine
AU  - Bange, Gert
AU  - Nikolić, Katarina
AU  - Ryu, Soojin
AU  - Dou, Yali
AU  - Essen, Lars-Oliver
AU  - Vázquez, Olalla
PY  - 2022
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4904
AB  - Optical control has enabled functional modulation
in cell culture with unparalleled spatiotemporal resolution.
However, current tools for in vivo manipulation are scarce. Here,
we design and implement a genuine on−of f optochemical probe
capable of achieving hematopoietic control in zebrafish. Our
photopharmacological approach first developed conformationally
strained visible light photoswitches (CS-VIPs) as inhibitors of the
histone methyltransferase MLL1 (KMT2A). In blood homeostasis
MLL1 plays a crucial yet controversial role. CS-VIP 8 optimally
fulfils the requirements of a true bistable functional system in vivo under visible-light irradiation, and with unprecedented stability.
These properties are exemplified via hematopoiesis photoinhibition with a single isomer in zebrafish. The present interdisciplinary
study uncovers the mechanism of action of CS-VIPs. Upon WDR5 binding, CS-VIP 8 causes MLL1 release with concomitant
allosteric rearrangements in the WDR5/RbBP5 interface. Since our tool provides on-demand reversible control without genetic
intervention or continuous irradiation, it will foster hematopathology and epigenetic investigations. Furthermore, our workflow will
enable exquisite photocontrol over other targets inhibited by macrocycles.
PB  - American Chemical Society
T2  - ACS Central Science
T1  - Bistable Photoswitch Allows in Vivo Control of Hematopoiesis
VL  - 8
IS  - 1
SP  - 57
EP  - 66
DO  - 10.1021/acscentsci.1c00434
ER  - 

@article{
author = "Albert, Lea and Nagpal, Jatin and Steinchen, Wieland and Zhang, Lei and Werel, Laura and Đoković, Nemanja and Ružić, Dušan and Hoffarth, Malte and Xu, Jing and Kaspareit, Johanna and Abendroth, Frank and Royant, Antoine and Bange, Gert and Nikolić, Katarina and Ryu, Soojin and Dou, Yali and Essen, Lars-Oliver and Vázquez, Olalla",
year = "2022",
abstract = "Optical control has enabled functional modulation
in cell culture with unparalleled spatiotemporal resolution.
However, current tools for in vivo manipulation are scarce. Here,
we design and implement a genuine on−of f optochemical probe
capable of achieving hematopoietic control in zebrafish. Our
photopharmacological approach first developed conformationally
strained visible light photoswitches (CS-VIPs) as inhibitors of the
histone methyltransferase MLL1 (KMT2A). In blood homeostasis
MLL1 plays a crucial yet controversial role. CS-VIP 8 optimally
fulfils the requirements of a true bistable functional system in vivo under visible-light irradiation, and with unprecedented stability.
These properties are exemplified via hematopoiesis photoinhibition with a single isomer in zebrafish. The present interdisciplinary
study uncovers the mechanism of action of CS-VIPs. Upon WDR5 binding, CS-VIP 8 causes MLL1 release with concomitant
allosteric rearrangements in the WDR5/RbBP5 interface. Since our tool provides on-demand reversible control without genetic
intervention or continuous irradiation, it will foster hematopathology and epigenetic investigations. Furthermore, our workflow will
enable exquisite photocontrol over other targets inhibited by macrocycles.",
publisher = "American Chemical Society",
journal = "ACS Central Science",
title = "Bistable Photoswitch Allows in Vivo Control of Hematopoiesis",
volume = "8",
number = "1",
pages = "57-66",
doi = "10.1021/acscentsci.1c00434"
}

Albert, L., Nagpal, J., Steinchen, W., Zhang, L., Werel, L., Đoković, N., Ružić, D., Hoffarth, M., Xu, J., Kaspareit, J., Abendroth, F., Royant, A., Bange, G., Nikolić, K., Ryu, S., Dou, Y., Essen, L.,& Vázquez, O.. (2022). Bistable Photoswitch Allows in Vivo Control of Hematopoiesis. in ACS Central Science
American Chemical Society., 8(1), 57-66.
https://doi.org/10.1021/acscentsci.1c00434

Albert L, Nagpal J, Steinchen W, Zhang L, Werel L, Đoković N, Ružić D, Hoffarth M, Xu J, Kaspareit J, Abendroth F, Royant A, Bange G, Nikolić K, Ryu S, Dou Y, Essen L, Vázquez O. Bistable Photoswitch Allows in Vivo Control of Hematopoiesis. in ACS Central Science. 2022;8(1):57-66.
doi:10.1021/acscentsci.1c00434 .

Albert, Lea, Nagpal, Jatin, Steinchen, Wieland, Zhang, Lei, Werel, Laura, Đoković, Nemanja, Ružić, Dušan, Hoffarth, Malte, Xu, Jing, Kaspareit, Johanna, Abendroth, Frank, Royant, Antoine, Bange, Gert, Nikolić, Katarina, Ryu, Soojin, Dou, Yali, Essen, Lars-Oliver, Vázquez, Olalla, "Bistable Photoswitch Allows in Vivo Control of Hematopoiesis" in ACS Central Science, 8, no. 1 (2022):57-66,
https://doi.org/10.1021/acscentsci.1c00434 . .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Srdić-Rajić, Tatjana
AU  - Nikolić, Katarina
PY  - 2022
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  - 8th Conference of the Young Chemists of Serbia, Book of Abstracts
T1  - Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors
SP  - 15
EP  - 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",
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 = "8th Conference of the Young Chemists of Serbia, Book of Abstracts",
title = "Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors",
pages = "15-15",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4737"
}

Ružić, D., Đoković, N., Srdić-Rajić, T.,& Nikolić, K.. (2022). Epigenetic drug discovery: fragment-based drug design of novel 1-benzhydryl-piperazine derivatives as selective histone deacetylase 6 inhibitors. in 8th Conference of the Young Chemists of Serbia, Book of Abstracts
Serbian Chemical Society and Serbian Young Chemists’ Club., 15-15.
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 8th Conference of the Young Chemists of Serbia, Book of Abstracts. 2022;:15-15.
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 8th Conference of the Young Chemists of Serbia, Book of Abstracts (2022):15-15,
https://hdl.handle.net/21.15107/rcub_farfar_4737 .

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  - Bošković, Jelena
AU  - Ružić, Dušan
AU  - Čudina, Olivera
AU  - Nikolić, Katarina
AU  - Dobričić, Vladimir
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4939
AB  - Inflammation has an important function in progression of some diseases, such as cancer. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) pathways provides a rational strategy for development of more effective and safer anti-inflammatory drugs. It is assumed that compounds bearing sulfohydroxamic acid chelate catalytic iron inside 5-LOX enzyme and there are only few publications about performed molecular docking studies on these compounds. The main aim of our study was to establish valid and accurate molecular docking platform for future in silico screening and design of promising dual COX-2 and 5-LOX inhibitors with terminal sulfohydroxamic group. GOLD (Genetic Optimisation for Ligand Docking) software v.5.7 was used in order to predict the binding modes and docking poses of previously published dual COX-2 and 5-LOX inhibitors compounds in the active sites of COX-1, COX-2 and 5-LOX enzymes. Crystal structures were downloaded from the PDB website: 5WBE (for COX-1), 1CX2 (for COX-2) and 3O8Y (for 5-LOX). The first step was to investigate binding modes and docking poses of sulfohydroxamic analogues taken from literature, which expressed dual COX-2 and 5-LOX inhibitory activities and to establish correlation between experimentally obtained inhibitory activities and calculated scoring functions (ChemPLP for COX-1 and COX-2 enzymes, ASPFF for 5-LOX enzyme). Nine newly designed sulfohydroxamic analogues were docked into COX-1, COX-2 and 5-LOX enzymes. In the case of COX-2 enzyme, all designed compounds showed the same binding pattern as the co-crystalized ligand, SC-558, while no significant interactions were observed in the COX-1 enzyme. The compounds had lower ChemPLP scores when docked into COX-1 enzyme comparing to COX-2, which indicated good in silico predicted COX-2 selectivity. Obtained ASPFF and docking poses indicate that these compounds are potential 5-LOX chelating inhibitors. In this study, we developed valid molecular docking models to accelerate in silico identification and design of dual COX-2 and 5-LOX inhibitors bearing sulfohydroxamic acids.
C3  - Paul Ehrlich (PE) Euro-PhD Network virtual meeting (PEVM2021), July 26th-28th, 2021
T1  - Design of dual cyclooxygenase-2 and 5-lipoxygenase inhibitors with iron-chelating properties – molecular docking
SP  - 52
EP  - 52
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4939
ER  - 

@conference{
author = "Bošković, Jelena and Ružić, Dušan and Čudina, Olivera and Nikolić, Katarina and Dobričić, Vladimir",
year = "2021",
abstract = "Inflammation has an important function in progression of some diseases, such as cancer. Dual inhibition of cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) pathways provides a rational strategy for development of more effective and safer anti-inflammatory drugs. It is assumed that compounds bearing sulfohydroxamic acid chelate catalytic iron inside 5-LOX enzyme and there are only few publications about performed molecular docking studies on these compounds. The main aim of our study was to establish valid and accurate molecular docking platform for future in silico screening and design of promising dual COX-2 and 5-LOX inhibitors with terminal sulfohydroxamic group. GOLD (Genetic Optimisation for Ligand Docking) software v.5.7 was used in order to predict the binding modes and docking poses of previously published dual COX-2 and 5-LOX inhibitors compounds in the active sites of COX-1, COX-2 and 5-LOX enzymes. Crystal structures were downloaded from the PDB website: 5WBE (for COX-1), 1CX2 (for COX-2) and 3O8Y (for 5-LOX). The first step was to investigate binding modes and docking poses of sulfohydroxamic analogues taken from literature, which expressed dual COX-2 and 5-LOX inhibitory activities and to establish correlation between experimentally obtained inhibitory activities and calculated scoring functions (ChemPLP for COX-1 and COX-2 enzymes, ASPFF for 5-LOX enzyme). Nine newly designed sulfohydroxamic analogues were docked into COX-1, COX-2 and 5-LOX enzymes. In the case of COX-2 enzyme, all designed compounds showed the same binding pattern as the co-crystalized ligand, SC-558, while no significant interactions were observed in the COX-1 enzyme. The compounds had lower ChemPLP scores when docked into COX-1 enzyme comparing to COX-2, which indicated good in silico predicted COX-2 selectivity. Obtained ASPFF and docking poses indicate that these compounds are potential 5-LOX chelating inhibitors. In this study, we developed valid molecular docking models to accelerate in silico identification and design of dual COX-2 and 5-LOX inhibitors bearing sulfohydroxamic acids.",
journal = "Paul Ehrlich (PE) Euro-PhD Network virtual meeting (PEVM2021), July 26th-28th, 2021",
title = "Design of dual cyclooxygenase-2 and 5-lipoxygenase inhibitors with iron-chelating properties – molecular docking",
pages = "52-52",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4939"
}

Bošković, J., Ružić, D., Čudina, O., Nikolić, K.,& Dobričić, V.. (2021). Design of dual cyclooxygenase-2 and 5-lipoxygenase inhibitors with iron-chelating properties – molecular docking. in Paul Ehrlich (PE) Euro-PhD Network virtual meeting (PEVM2021), July 26th-28th, 2021, 52-52.
https://hdl.handle.net/21.15107/rcub_farfar_4939

Bošković J, Ružić D, Čudina O, Nikolić K, Dobričić V. Design of dual cyclooxygenase-2 and 5-lipoxygenase inhibitors with iron-chelating properties – molecular docking. in Paul Ehrlich (PE) Euro-PhD Network virtual meeting (PEVM2021), July 26th-28th, 2021. 2021;:52-52.
https://hdl.handle.net/21.15107/rcub_farfar_4939 .

Bošković, Jelena, Ružić, Dušan, Čudina, Olivera, Nikolić, Katarina, Dobričić, Vladimir, "Design of dual cyclooxygenase-2 and 5-lipoxygenase inhibitors with iron-chelating properties – molecular docking" in Paul Ehrlich (PE) Euro-PhD Network virtual meeting (PEVM2021), July 26th-28th, 2021 (2021):52-52,
https://hdl.handle.net/21.15107/rcub_farfar_4939 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Ružić, Dušan
AU  - Đikić, Teodora
AU  - Cvijić, Sandra
AU  - Ignjatović, Jelisaveta
AU  - Ibrić, Svetlana
AU  - Baralić, Katarina
AU  - Buha-Đorđević, Aleksandra
AU  - Ćurčić, Marijana
AU  - Đukić-Ćosić, Danijela
AU  - Nikolić, Katarina
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4896
PB  - Hellenic Society of Medicinal Chemistry
C3  - 18th Hellenic Symposium on Medicinal Chemistry, 25 - 27 February 2021, Online Symposium
T1  - Seeking SARS-CoV-2 Mpro inhibitors through an integrative in silico approach
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4896
ER  - 

@conference{
author = "Đoković, Nemanja and Ružić, Dušan and Đikić, Teodora and Cvijić, Sandra and Ignjatović, Jelisaveta and Ibrić, Svetlana and Baralić, Katarina and Buha-Đorđević, Aleksandra and Ćurčić, Marijana and Đukić-Ćosić, Danijela and Nikolić, Katarina",
year = "2021",
publisher = "Hellenic Society of Medicinal Chemistry",
journal = "18th Hellenic Symposium on Medicinal Chemistry, 25 - 27 February 2021, Online Symposium",
title = "Seeking SARS-CoV-2 Mpro inhibitors through an integrative in silico approach",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4896"
}

Đoković, N., Ružić, D., Đikić, T., Cvijić, S., Ignjatović, J., Ibrić, S., Baralić, K., Buha-Đorđević, A., Ćurčić, M., Đukić-Ćosić, D.,& Nikolić, K.. (2021). Seeking SARS-CoV-2 Mpro inhibitors through an integrative in silico approach. in 18th Hellenic Symposium on Medicinal Chemistry, 25 - 27 February 2021, Online Symposium
Hellenic Society of Medicinal Chemistry..
https://hdl.handle.net/21.15107/rcub_farfar_4896

Đoković N, Ružić D, Đikić T, Cvijić S, Ignjatović J, Ibrić S, Baralić K, Buha-Đorđević A, Ćurčić M, Đukić-Ćosić D, Nikolić K. Seeking SARS-CoV-2 Mpro inhibitors through an integrative in silico approach. in 18th Hellenic Symposium on Medicinal Chemistry, 25 - 27 February 2021, Online Symposium. 2021;.
https://hdl.handle.net/21.15107/rcub_farfar_4896 .

Đoković, Nemanja, Ružić, Dušan, Đikić, Teodora, Cvijić, Sandra, Ignjatović, Jelisaveta, Ibrić, Svetlana, Baralić, Katarina, Buha-Đorđević, Aleksandra, Ćurčić, Marijana, Đukić-Ćosić, Danijela, Nikolić, Katarina, "Seeking SARS-CoV-2 Mpro inhibitors through an integrative in silico approach" in 18th Hellenic Symposium on Medicinal Chemistry, 25 - 27 February 2021, Online Symposium (2021),
https://hdl.handle.net/21.15107/rcub_farfar_4896 .