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  - 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  - Zhang, Lei
AU  - Xie, Xiulan
AU  - Đoković, Nemanja
AU  - Nikolić, Katarina
AU  - Kosenkov, Dmitri
AU  - Abendroth, Frank
AU  - Vázquez, Olalla
PY  - 2023
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4913
AB  - Dynamics are intrinsic to both RNA function and
structure. Yet, the available means to precisely provide RNA-based
processes with spatiotemporal resolution are scarce. Here, our
work pioneers a reversible approach to regulate RNA splicing
within primary patient-derived cells by synthetic photoswitches.
Our small molecule enables conditional real-time control at mRNA
and protein levels. NMR experiments, together with theoretical
calculations, photochemical characterization, fluorescence polarization
measurements, and living cell-based assays, confirmed lightdependent
exon inclusion as well as an increase in the target
functional protein. Therefore, we first demonstrated the potential
of photopharmacology modulation in splicing, tweaking the
current optochemical toolkit. The timeliness on the consolidation
of RNA research as the driving force toward therapeutical innovation holds the promise that our approach will contribute to
redrawing the vision of RNA.
PB  - American Chemical Society
T2  - Journal of the American Chemical Society
T1  - Reversible Control of RNA Splicing by Photoswitchable Small Molecules
VL  - 145
IS  - 23
SP  - 12783
EP  - 12792
DO  - 10.1021/jacs.3c03275
ER  - 

@article{
author = "Zhang, Lei and Xie, Xiulan and Đoković, Nemanja and Nikolić, Katarina and Kosenkov, Dmitri and Abendroth, Frank and Vázquez, Olalla",
year = "2023",
abstract = "Dynamics are intrinsic to both RNA function and
structure. Yet, the available means to precisely provide RNA-based
processes with spatiotemporal resolution are scarce. Here, our
work pioneers a reversible approach to regulate RNA splicing
within primary patient-derived cells by synthetic photoswitches.
Our small molecule enables conditional real-time control at mRNA
and protein levels. NMR experiments, together with theoretical
calculations, photochemical characterization, fluorescence polarization
measurements, and living cell-based assays, confirmed lightdependent
exon inclusion as well as an increase in the target
functional protein. Therefore, we first demonstrated the potential
of photopharmacology modulation in splicing, tweaking the
current optochemical toolkit. The timeliness on the consolidation
of RNA research as the driving force toward therapeutical innovation holds the promise that our approach will contribute to
redrawing the vision of RNA.",
publisher = "American Chemical Society",
journal = "Journal of the American Chemical Society",
title = "Reversible Control of RNA Splicing by Photoswitchable Small Molecules",
volume = "145",
number = "23",
pages = "12783-12792",
doi = "10.1021/jacs.3c03275"
}

Zhang, L., Xie, X., Đoković, N., Nikolić, K., Kosenkov, D., Abendroth, F.,& Vázquez, O.. (2023). Reversible Control of RNA Splicing by Photoswitchable Small Molecules. in Journal of the American Chemical Society
American Chemical Society., 145(23), 12783-12792.
https://doi.org/10.1021/jacs.3c03275

Zhang L, Xie X, Đoković N, Nikolić K, Kosenkov D, Abendroth F, Vázquez O. Reversible Control of RNA Splicing by Photoswitchable Small Molecules. in Journal of the American Chemical Society. 2023;145(23):12783-12792.
doi:10.1021/jacs.3c03275 .

Zhang, Lei, Xie, Xiulan, Đoković, Nemanja, Nikolić, Katarina, Kosenkov, Dmitri, Abendroth, Frank, Vázquez, Olalla, "Reversible Control of RNA Splicing by Photoswitchable Small Molecules" in Journal of the American Chemical Society, 145, no. 23 (2023):12783-12792,
https://doi.org/10.1021/jacs.3c03275 . .

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

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

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

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

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

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

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

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

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

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

TY  - 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  - 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  - 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  - JOUR
AU  - Elek, Milica
AU  - Đoković, Nemanja
AU  - Frank, Annika
AU  - Oljačić, Slavica
AU  - Živković, Aleksandra
AU  - Nikolić, Katarina
AU  - Stark, Holger
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3793
AB  - Dopamine is an important neurotransmitter in the human brain and its altered concentrations can lead to various neurological diseases. We studied the binding of novel compounds at the dopamine D2 (D2R) and D3 (D3R) receptor subtypes, which belong to the D2-like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed. Novel ligands were docked into the D2R and D3R crystal structures to examine the precise binding mode. A quantum mechanics/molecular mechanics study was performed to gain insights into the nature of the intermolecular interactions between the newly introduced pentafluorosulfanyl (SF5) moiety and D2R and D3R. A radioligand displacement assay determined that all of the ligands showed moderate-to-low nanomolar affinities at D2R and D3R, with a slight preference for D3R, which was confirmed in the in silico studies. N-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-4-(pentafluoro-λ6-sulfanyl)benzamide (7i) showed the highest D3R affinity and selectivity (pKi values of 7.14 [D2R] and 8.42 [D3R]).
PB  - Wiley-VCH Verlag
T2  - Archiv der Pharmazie
T1  - Synthesis, in silico, and in vitro studies of novel dopamine D2 and D3 receptor ligands
DO  - 10.1002/ardp.202000486
ER  - 

@article{
author = "Elek, Milica and Đoković, Nemanja and Frank, Annika and Oljačić, Slavica and Živković, Aleksandra and Nikolić, Katarina and Stark, Holger",
year = "2021",
abstract = "Dopamine is an important neurotransmitter in the human brain and its altered concentrations can lead to various neurological diseases. We studied the binding of novel compounds at the dopamine D2 (D2R) and D3 (D3R) receptor subtypes, which belong to the D2-like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed. Novel ligands were docked into the D2R and D3R crystal structures to examine the precise binding mode. A quantum mechanics/molecular mechanics study was performed to gain insights into the nature of the intermolecular interactions between the newly introduced pentafluorosulfanyl (SF5) moiety and D2R and D3R. A radioligand displacement assay determined that all of the ligands showed moderate-to-low nanomolar affinities at D2R and D3R, with a slight preference for D3R, which was confirmed in the in silico studies. N-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-4-(pentafluoro-λ6-sulfanyl)benzamide (7i) showed the highest D3R affinity and selectivity (pKi values of 7.14 [D2R] and 8.42 [D3R]).",
publisher = "Wiley-VCH Verlag",
journal = "Archiv der Pharmazie",
title = "Synthesis, in silico, and in vitro studies of novel dopamine D2 and D3 receptor ligands",
doi = "10.1002/ardp.202000486"
}

Elek, M., Đoković, N., Frank, A., Oljačić, S., Živković, A., Nikolić, K.,& Stark, H.. (2021). Synthesis, in silico, and in vitro studies of novel dopamine D2 and D3 receptor ligands. in Archiv der Pharmazie
Wiley-VCH Verlag..
https://doi.org/10.1002/ardp.202000486

Elek M, Đoković N, Frank A, Oljačić S, Živković A, Nikolić K, Stark H. Synthesis, in silico, and in vitro studies of novel dopamine D2 and D3 receptor ligands. in Archiv der Pharmazie. 2021;.
doi:10.1002/ardp.202000486 .

Elek, Milica, Đoković, Nemanja, Frank, Annika, Oljačić, Slavica, Živković, Aleksandra, Nikolić, Katarina, Stark, Holger, "Synthesis, in silico, and in vitro studies of novel dopamine D2 and D3 receptor ligands" in Archiv der Pharmazie (2021),
https://doi.org/10.1002/ardp.202000486 . .

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 .

TY  - JOUR
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/123456789/3830
AB  - Considering the urgent need for novel therapeutics in ongoing COVID-19 pandemic, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we designed an integrative in silico drug repurposing approach for rapid selection of potential candidates against SARS-CoV-2 Main Protease (Mpro). To screen FDA-approved drugs, we implemented structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data mining analysis of drug-gene-COVID-19 association. Through presented approach, we selected the most promising FDA approved drugs for further COVID-19 drug development campaigns and analysed them in context of available experimental data. To the best of our knowledge, this is unique in silico study which integrates structure-based molecular modeling of Mpro inhibitors with predictions of their tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects of selected candidates.
PB  - John Wiley and Sons Inc
T2  - Molecular Informatics
T1  - An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease
VL  - 40
IS  - 5
DO  - 10.1002/minf.202000187
ER  - 

@article{
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",
abstract = "Considering the urgent need for novel therapeutics in ongoing COVID-19 pandemic, drug repurposing approach might offer rapid solutions comparing to de novo drug design. In this study, we designed an integrative in silico drug repurposing approach for rapid selection of potential candidates against SARS-CoV-2 Main Protease (Mpro). To screen FDA-approved drugs, we implemented structure-based molecular modelling techniques, physiologically-based pharmacokinetic (PBPK) modelling of drugs disposition and data mining analysis of drug-gene-COVID-19 association. Through presented approach, we selected the most promising FDA approved drugs for further COVID-19 drug development campaigns and analysed them in context of available experimental data. To the best of our knowledge, this is unique in silico study which integrates structure-based molecular modeling of Mpro inhibitors with predictions of their tissue disposition, drug-gene-COVID-19 associations and prediction of pleiotropic effects of selected candidates.",
publisher = "John Wiley and Sons Inc",
journal = "Molecular Informatics",
title = "An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease",
volume = "40",
number = "5",
doi = "10.1002/minf.202000187"
}

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). An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease. in Molecular Informatics
John Wiley and Sons Inc., 40(5).
https://doi.org/10.1002/minf.202000187

Đoković N, Ružić D, Đikić T, Cvijić S, Ignjatović J, Ibrić S, Baralić K, Buha-Đorđević A, Ćurčić M, Đukić-Ćosić D, Nikolić K. An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease. in Molecular Informatics. 2021;40(5).
doi:10.1002/minf.202000187 .

Đoković, Nemanja, Ružić, Dušan, Đikić, Teodora, Cvijić, Sandra, Ignjatović, Jelisaveta, Ibrić, Svetlana, Baralić, Katarina, Buha-Đorđević, Aleksandra, Ćurčić, Marijana, Đukić-Ćosić, Danijela, Nikolić, Katarina, "An Integrative in silico Drug Repurposing Approach for Identification of Potential Inhibitors of SARS-CoV-2 Main Protease" in Molecular Informatics, 40, no. 5 (2021),
https://doi.org/10.1002/minf.202000187 . .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Corentin, Bon
AU  - Petković, Miloš
AU  - Ellinger, Bertrand
AU  - Gul, Sheraz
AU  - Santibanez, Juan
AU  - Lahtela-Kakkonen, Maija
AU  - Halby, Ludovic
AU  - Ganesan, A.
AU  - Srdić Rajić, Tatjana
AU  - Arimondo, Paola
AU  - Nikolić, Katarina
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4938
C3  - e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021
T1  - Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4938
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Corentin, Bon and Petković, Miloš and Ellinger, Bertrand and Gul, Sheraz and Santibanez, Juan and Lahtela-Kakkonen, Maija and Halby, Ludovic and Ganesan, A. and Srdić Rajić, Tatjana and Arimondo, Paola and Nikolić, Katarina",
year = "2021",
journal = "e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021",
title = "Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4938"
}

Ružić, D., Đoković, N., Corentin, B., Petković, M., Ellinger, B., Gul, S., Santibanez, J., Lahtela-Kakkonen, M., Halby, L., Ganesan, A., Srdić Rajić, T., Arimondo, P.,& Nikolić, K.. (2021). Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors. in e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021.
https://hdl.handle.net/21.15107/rcub_farfar_4938

Ružić D, Đoković N, Corentin B, Petković M, Ellinger B, Gul S, Santibanez J, Lahtela-Kakkonen M, Halby L, Ganesan A, Srdić Rajić T, Arimondo P, Nikolić K. Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors. in e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021. 2021;.
https://hdl.handle.net/21.15107/rcub_farfar_4938 .

Ružić, Dušan, Đoković, Nemanja, Corentin, Bon, Petković, Miloš, Ellinger, Bertrand, Gul, Sheraz, Santibanez, Juan, Lahtela-Kakkonen, Maija, Halby, Ludovic, Ganesan, A., Srdić Rajić, Tatjana, Arimondo, Paola, Nikolić, Katarina, "Epigenetic drug discovery: Successful examples of Computer-Aided Drug Designing of Histone Deacetylase (HDAC6 and SIRT2) and Histone Methyltransferase (DOT1L) inhibitors" in e-EuCo-CTC 2021, Online conference, EuChemS Division of Computational and Theoretical Chemistry, November 18-19 2021 (2021),
https://hdl.handle.net/21.15107/rcub_farfar_4938 .

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

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

Ružić, D., Đoković, N., Petković, M., Agbaba, D., Gul, S., Lahtela‐Kakkonen, M., Ganesan, A., Santibanez, J., Srdić-Rajić, T.,& Nikolić, K.. (2021). Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors. in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts
EFMC-ISMC., 360-360.
https://hdl.handle.net/21.15107/rcub_farfar_4889

Ružić D, Đoković N, Petković M, Agbaba D, Gul S, Lahtela‐Kakkonen M, Ganesan A, Santibanez J, Srdić-Rajić T, Nikolić K. Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors. in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts. 2021;:360-360.
https://hdl.handle.net/21.15107/rcub_farfar_4889 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Gul, Sheraz, Lahtela‐Kakkonen, Maija, Ganesan, A., Santibanez, Juan, Srdić-Rajić, Tatjana, Nikolić, Katarina, "Rational design, synthesis and in vitro testing of selective HDAC6 and SIRT2 inhibitors" in EFMC-ISMC, XXVI EFMC International Symposium on Medicinal Chemistry, Book of Abstracts (2021):360-360,
https://hdl.handle.net/21.15107/rcub_farfar_4889 .

TY  - JOUR
AU  - Asanović, Igor
AU  - Strandback, Emilia
AU  - Kroupova, Alena
AU  - Pasajlić, Đurđa
AU  - Meinhart, Anton
AU  - Tsung-Pin, Pai
AU  - Đoković, Nemanja
AU  - Anrather, Dorothea
AU  - Schuetz, Thomas
AU  - Suskiewicz, Marcin Jozef
AU  - Sillamaa, Sirelin
AU  - Kocher, Thomas
AU  - Beveridge, Rebecca
AU  - Nikolić, Katarina
AU  - Schleiffer, Alexander
AU  - Jinek, Martin
AU  - Hartl, Markus
AU  - Clausen, Tim
AU  - Penninger, Josef
AU  - Macheroux, Peter
AU  - Weitzer, Stefan
AU  - Martinez, Javier
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4905
AB  - The tRNA ligase complex (tRNA-LC) splices precursor tRNAs (pre-tRNA), and Xbp1-mRNA during the
unfolded protein response (UPR). In aerobic conditions, a cysteine residue bound to two metal ions in its
ancient, catalytic subunit RTCB could make the tRNA-LC susceptible to oxidative inactivation. Here, we
confirm this hypothesis and reveal a co-evolutionary association between the tRNA-LC and PYROXD1, a
conserved and essential oxidoreductase. We reveal that PYROXD1 preserves the activity of the mammalian
tRNA-LC in pre-tRNA splicing and UPR. PYROXD1 binds the tRNA-LC in the presence of NAD(P)H and converts
RTCB-bound NAD(P)H into NAD(P)+, a typical oxidative co-enzyme. However, NAD(P)+ here acts as an
antioxidant and protects the tRNA-LC from oxidative inactivation, which is dependent on copper ions.
Genetic variants of PYROXD1 that cause human myopathies only partially support tRNA-LC activity. Thus,
we establish the tRNA-LC as an oxidation-sensitive metalloenzyme, safeguarded by the flavoprotein
PYROXD1 through an unexpected redox mechanism.
PB  - Elsevier
T2  - Molecular Cell
T1  - The oxidoreductase PYROXD1 uses NAD(P)+ as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response
VL  - 81
IS  - 12
SP  - 2520
EP  - 2532
DO  - 10.1016/j.molcel.2021.04.007
ER  - 

@article{
author = "Asanović, Igor and Strandback, Emilia and Kroupova, Alena and Pasajlić, Đurđa and Meinhart, Anton and Tsung-Pin, Pai and Đoković, Nemanja and Anrather, Dorothea and Schuetz, Thomas and Suskiewicz, Marcin Jozef and Sillamaa, Sirelin and Kocher, Thomas and Beveridge, Rebecca and Nikolić, Katarina and Schleiffer, Alexander and Jinek, Martin and Hartl, Markus and Clausen, Tim and Penninger, Josef and Macheroux, Peter and Weitzer, Stefan and Martinez, Javier",
year = "2021",
abstract = "The tRNA ligase complex (tRNA-LC) splices precursor tRNAs (pre-tRNA), and Xbp1-mRNA during the
unfolded protein response (UPR). In aerobic conditions, a cysteine residue bound to two metal ions in its
ancient, catalytic subunit RTCB could make the tRNA-LC susceptible to oxidative inactivation. Here, we
confirm this hypothesis and reveal a co-evolutionary association between the tRNA-LC and PYROXD1, a
conserved and essential oxidoreductase. We reveal that PYROXD1 preserves the activity of the mammalian
tRNA-LC in pre-tRNA splicing and UPR. PYROXD1 binds the tRNA-LC in the presence of NAD(P)H and converts
RTCB-bound NAD(P)H into NAD(P)+, a typical oxidative co-enzyme. However, NAD(P)+ here acts as an
antioxidant and protects the tRNA-LC from oxidative inactivation, which is dependent on copper ions.
Genetic variants of PYROXD1 that cause human myopathies only partially support tRNA-LC activity. Thus,
we establish the tRNA-LC as an oxidation-sensitive metalloenzyme, safeguarded by the flavoprotein
PYROXD1 through an unexpected redox mechanism.",
publisher = "Elsevier",
journal = "Molecular Cell",
title = "The oxidoreductase PYROXD1 uses NAD(P)+ as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response",
volume = "81",
number = "12",
pages = "2520-2532",
doi = "10.1016/j.molcel.2021.04.007"
}

Asanović, I., Strandback, E., Kroupova, A., Pasajlić, Đ., Meinhart, A., Tsung-Pin, P., Đoković, N., Anrather, D., Schuetz, T., Suskiewicz, M. J., Sillamaa, S., Kocher, T., Beveridge, R., Nikolić, K., Schleiffer, A., Jinek, M., Hartl, M., Clausen, T., Penninger, J., Macheroux, P., Weitzer, S.,& Martinez, J.. (2021). The oxidoreductase PYROXD1 uses NAD(P)+ as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response. in Molecular Cell
Elsevier., 81(12), 2520-2532.
https://doi.org/10.1016/j.molcel.2021.04.007

Asanović I, Strandback E, Kroupova A, Pasajlić Đ, Meinhart A, Tsung-Pin P, Đoković N, Anrather D, Schuetz T, Suskiewicz MJ, Sillamaa S, Kocher T, Beveridge R, Nikolić K, Schleiffer A, Jinek M, Hartl M, Clausen T, Penninger J, Macheroux P, Weitzer S, Martinez J. The oxidoreductase PYROXD1 uses NAD(P)+ as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response. in Molecular Cell. 2021;81(12):2520-2532.
doi:10.1016/j.molcel.2021.04.007 .

Asanović, Igor, Strandback, Emilia, Kroupova, Alena, Pasajlić, Đurđa, Meinhart, Anton, Tsung-Pin, Pai, Đoković, Nemanja, Anrather, Dorothea, Schuetz, Thomas, Suskiewicz, Marcin Jozef, Sillamaa, Sirelin, Kocher, Thomas, Beveridge, Rebecca, Nikolić, Katarina, Schleiffer, Alexander, Jinek, Martin, Hartl, Markus, Clausen, Tim, Penninger, Josef, Macheroux, Peter, Weitzer, Stefan, Martinez, Javier, "The oxidoreductase PYROXD1 uses NAD(P)+ as an antioxidant to sustain tRNA ligase activity in pre-tRNA splicing and unfolded protein response" in Molecular Cell, 81, no. 12 (2021):2520-2532,
https://doi.org/10.1016/j.molcel.2021.04.007 . .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Postolović, Ana
AU  - Nikolić, Katarina
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4857
AB  - The group of 5 [(amidobenzyl)oxy] nicotinamides
(SIRT2) inhibitors. Despite structural similarity, representatives of this group of inhibitors
displayed versatile mechanisms of inhibition which hamper rational drug design. The aim of
this research was to form a 3D-QSAR (3D-Quantitative Structure-Activity Relationship)
model, define the pharmacophore of this subgroup of SIRT2 inhibitors, define the mode of
protein-ligand interactions and design new compounds with improved predicted activity and
pharmacokinetics. For the 3D-QSAR study, data set was generated using structures and
-conformations of compounds were
optimized, alignment-independent GRIND2 descriptors were calculated and 3D-QSAR PLS
models were generated using 70% of data set. To investigate bioactive conformations of
inhibitors, molecular docking was used. Molecular docking analysis identified two clusters of
predicted bioactive conformations which is in alignment with experimental observations. The
defined pharmacophoric features were used to design novel inhibitors with improved predicted
potency and ADMET profiles.
PB  - Institute for Information Technologies, University of Kragujevac, Serbia
C3  - 1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS)
T1  - Molecular modeling of 5 [(amidobenzyl)oxy] nicotinamides as sirtuin 2 inhibitors using alignment - (in)dependent 3D-QSAR analysis and molecular docking
SP  - 410
EP  - 413
DO  - 10.46793/ICCBI21.410DJ
ER  - 

@conference{
author = "Đoković, Nemanja and Postolović, Ana and Nikolić, Katarina",
year = "2021",
abstract = "The group of 5 [(amidobenzyl)oxy] nicotinamides
(SIRT2) inhibitors. Despite structural similarity, representatives of this group of inhibitors
displayed versatile mechanisms of inhibition which hamper rational drug design. The aim of
this research was to form a 3D-QSAR (3D-Quantitative Structure-Activity Relationship)
model, define the pharmacophore of this subgroup of SIRT2 inhibitors, define the mode of
protein-ligand interactions and design new compounds with improved predicted activity and
pharmacokinetics. For the 3D-QSAR study, data set was generated using structures and
-conformations of compounds were
optimized, alignment-independent GRIND2 descriptors were calculated and 3D-QSAR PLS
models were generated using 70% of data set. To investigate bioactive conformations of
inhibitors, molecular docking was used. Molecular docking analysis identified two clusters of
predicted bioactive conformations which is in alignment with experimental observations. The
defined pharmacophoric features were used to design novel inhibitors with improved predicted
potency and ADMET profiles.",
publisher = "Institute for Information Technologies, University of Kragujevac, Serbia",
journal = "1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS)",
title = "Molecular modeling of 5 [(amidobenzyl)oxy] nicotinamides as sirtuin 2 inhibitors using alignment - (in)dependent 3D-QSAR analysis and molecular docking",
pages = "410-413",
doi = "10.46793/ICCBI21.410DJ"
}

Đoković, N., Postolović, A.,& Nikolić, K.. (2021). Molecular modeling of 5 [(amidobenzyl)oxy] nicotinamides as sirtuin 2 inhibitors using alignment - (in)dependent 3D-QSAR analysis and molecular docking. in 1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS)
Institute for Information Technologies, University of Kragujevac, Serbia., 410-413.
https://doi.org/10.46793/ICCBI21.410DJ

Đoković N, Postolović A, Nikolić K. Molecular modeling of 5 [(amidobenzyl)oxy] nicotinamides as sirtuin 2 inhibitors using alignment - (in)dependent 3D-QSAR analysis and molecular docking. in 1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS). 2021;:410-413.
doi:10.46793/ICCBI21.410DJ .

Đoković, Nemanja, Postolović, Ana, Nikolić, Katarina, "Molecular modeling of 5 [(amidobenzyl)oxy] nicotinamides as sirtuin 2 inhibitors using alignment - (in)dependent 3D-QSAR analysis and molecular docking" in 1st International Conference on Chemo and BioInformatics ICCBIKG 2021 (BOOK OF PROCEEDINGS) (2021):410-413,
https://doi.org/10.46793/ICCBI21.410DJ . .

TY  - JOUR
AU  - Bon, Corentin
AU  - Si, Yang
AU  - Pernak, Melanie
AU  - Barbachowska, Magdalena
AU  - Levi-Acobas, Eva
AU  - Cadet Daniel, Veronique
AU  - Jallet, Corinne
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Đikić, Teodora
AU  - Nikolić, Katarina
AU  - Halby, Ludovic
AU  - Arimondo, Paola B.
PY  - 2021
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3954
AB  - Histone methyltransferase DOT1L catalyzes mono-, di-and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.
PB  - MDPI
T2  - Molecules
T1  - Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein
VL  - 26
IS  - 17
DO  - 10.3390/molecules26175300
ER  - 

@article{
author = "Bon, Corentin and Si, Yang and Pernak, Melanie and Barbachowska, Magdalena and Levi-Acobas, Eva and Cadet Daniel, Veronique and Jallet, Corinne and Ružić, Dušan and Đoković, Nemanja and Đikić, Teodora and Nikolić, Katarina and Halby, Ludovic and Arimondo, Paola B.",
year = "2021",
abstract = "Histone methyltransferase DOT1L catalyzes mono-, di-and trimethylation of histone 3 at lysine residue 79 (H3K79) and hypermethylation of H3K79 has been linked to the development of acute leukemias characterized by the MLL (mixed-lineage leukemia) rearrangements (MLLr cells). The inhibition of H3K79 methylation inhibits MLLr cells proliferation, and an inhibitor specific for DOT1L, pinometostat, was in clinical trials (Phase Ib/II). However, the compound showed poor pharmacological properties. Thus, there is a need to find new potent inhibitors of DOT1L for the treatment of rearranged leukemias. Here we present the design, synthesis, and biological evaluation of a small molecule that inhibits in the nM level the enzymatic activity of hDOT1L, H3K79 methylation in MLLr cells with comparable potency to pinometostat, associated with improved metabolic stability and a characteristic cytostatic effect.",
publisher = "MDPI",
journal = "Molecules",
title = "Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein",
volume = "26",
number = "17",
doi = "10.3390/molecules26175300"
}

Bon, C., Si, Y., Pernak, M., Barbachowska, M., Levi-Acobas, E., Cadet Daniel, V., Jallet, C., Ružić, D., Đoković, N., Đikić, T., Nikolić, K., Halby, L.,& Arimondo, P. B.. (2021). Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein. in Molecules
MDPI., 26(17).
https://doi.org/10.3390/molecules26175300

Bon C, Si Y, Pernak M, Barbachowska M, Levi-Acobas E, Cadet Daniel V, Jallet C, Ružić D, Đoković N, Đikić T, Nikolić K, Halby L, Arimondo PB. Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein. in Molecules. 2021;26(17).
doi:10.3390/molecules26175300 .

Bon, Corentin, Si, Yang, Pernak, Melanie, Barbachowska, Magdalena, Levi-Acobas, Eva, Cadet Daniel, Veronique, Jallet, Corinne, Ružić, Dušan, Đoković, Nemanja, Đikić, Teodora, Nikolić, Katarina, Halby, Ludovic, Arimondo, Paola B., "Synthesis and biological activity of a cytostatic inhibitor of MLLr leukemia targeting the DOT1L protein" in Molecules, 26, no. 17 (2021),
https://doi.org/10.3390/molecules26175300 . .