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

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

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

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

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

TY  - CONF
AU  - 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  - CONF
AU  - Đoković, Nemanja
AU  - Rahnasto‐Rilla, Minna
AU  - Lahtela-Kakkonen, Maija
AU  - Nikolić, Katarina
PY  - 2020
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5402
PB  - EFMC-ISMC & EFMC-YMCS
C3  - EFMC-ISMC & EFMC-YMCS Virtual poster session Powered by the EFMC Young Scientists Network, September 9, 2020, Book of Abstracts
T1  - Exploring the chemical space of sirt2 inhibitors through biomolecular simulations
SP  - 112
EP  - 112
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5402
ER  - 

@conference{
author = "Đoković, Nemanja and Rahnasto‐Rilla, Minna and Lahtela-Kakkonen, Maija and Nikolić, Katarina",
year = "2020",
publisher = "EFMC-ISMC & EFMC-YMCS",
journal = "EFMC-ISMC & EFMC-YMCS Virtual poster session Powered by the EFMC Young Scientists Network, September 9, 2020, Book of Abstracts",
title = "Exploring the chemical space of sirt2 inhibitors through biomolecular simulations",
pages = "112-112",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5402"
}

Đoković, N., Rahnasto‐Rilla, M., Lahtela-Kakkonen, M.,& Nikolić, K.. (2020). Exploring the chemical space of sirt2 inhibitors through biomolecular simulations. in EFMC-ISMC & EFMC-YMCS Virtual poster session Powered by the EFMC Young Scientists Network, September 9, 2020, Book of Abstracts
EFMC-ISMC & EFMC-YMCS., 112-112.
https://hdl.handle.net/21.15107/rcub_farfar_5402

Đoković N, Rahnasto‐Rilla M, Lahtela-Kakkonen M, Nikolić K. Exploring the chemical space of sirt2 inhibitors through biomolecular simulations. in EFMC-ISMC & EFMC-YMCS Virtual poster session Powered by the EFMC Young Scientists Network, September 9, 2020, Book of Abstracts. 2020;:112-112.
https://hdl.handle.net/21.15107/rcub_farfar_5402 .

Đoković, Nemanja, Rahnasto‐Rilla, Minna, Lahtela-Kakkonen, Maija, Nikolić, Katarina, "Exploring the chemical space of sirt2 inhibitors through biomolecular simulations" in EFMC-ISMC & EFMC-YMCS Virtual poster session Powered by the EFMC Young Scientists Network, September 9, 2020, Book of Abstracts (2020):112-112,
https://hdl.handle.net/21.15107/rcub_farfar_5402 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Gul, Sheraz
AU  - Lahtela-Kakkonen, Maija
AU  - Ganesan, A.
AU  - Nikolić, Katarina
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4946
PB  - EuChemS (European Chemical Society)
C3  - 12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts
T1  - Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4946
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Gul, Sheraz and Lahtela-Kakkonen, Maija and Ganesan, A. and Nikolić, Katarina",
year = "2019",
publisher = "EuChemS (European Chemical Society)",
journal = "12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts",
title = "Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4946"
}

Ružić, D., Đoković, N., Petković, M., Agbaba, D., Gul, S., Lahtela-Kakkonen, M., Ganesan, A.,& Nikolić, K.. (2019). Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors. in 12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts
EuChemS (European Chemical Society)..
https://hdl.handle.net/21.15107/rcub_farfar_4946

Ružić D, Đoković N, Petković M, Agbaba D, Gul S, Lahtela-Kakkonen M, Ganesan A, Nikolić K. Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors. in 12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_4946 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Gul, Sheraz, Lahtela-Kakkonen, Maija, Ganesan, A., Nikolić, Katarina, "Computer-Aided Drug Design and Evaluation of Selective HDAC Inhibitors" in 12th European Conference on computational theoretical chemistry  (EUCO-CTC 2019), 1-5 September 2019, Perugia, Italy, Book of Abstracts (2019),
https://hdl.handle.net/21.15107/rcub_farfar_4946 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Gul, Sheraz
AU  - Lahtela-Kakkonen, Maija
AU  - Ganesan, A.
AU  - Nikolić, Katarina
PY  - 2019
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4945
PB  - European Cooperation in Science and Technology (COST)
C3  - COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019.
T1  - Rational design and evaluation of selective HDAC inhibitors
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4945
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Gul, Sheraz and Lahtela-Kakkonen, Maija and Ganesan, A. and Nikolić, Katarina",
year = "2019",
publisher = "European Cooperation in Science and Technology (COST)",
journal = "COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019.",
title = "Rational design and evaluation of selective HDAC inhibitors",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4945"
}

Ružić, D., Đoković, N., Petković, M., Agbaba, D., Gul, S., Lahtela-Kakkonen, M., Ganesan, A.,& Nikolić, K.. (2019). Rational design and evaluation of selective HDAC inhibitors. in COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019.
European Cooperation in Science and Technology (COST)..
https://hdl.handle.net/21.15107/rcub_farfar_4945

Ružić D, Đoković N, Petković M, Agbaba D, Gul S, Lahtela-Kakkonen M, Ganesan A, Nikolić K. Rational design and evaluation of selective HDAC inhibitors. in COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019.. 2019;.
https://hdl.handle.net/21.15107/rcub_farfar_4945 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Gul, Sheraz, Lahtela-Kakkonen, Maija, Ganesan, A., Nikolić, Katarina, "Rational design and evaluation of selective HDAC inhibitors" in COST Action CM1406 EpiChemBio WG1 meeting, Salerno, 4-5 March 2019. (2019),
https://hdl.handle.net/21.15107/rcub_farfar_4945 .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Lahtela-Kakkonen, Maija
AU  - Nikolić, Katarina
AU  - Ganesan, A.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4950
C3  - Epigenetic Chemical Biology – Action CM1406, Computational Methods in Drug Design. Training School 22 – 24 March 2018, Istanbul, Turkey
T1  - Computer-aided design of histone deacetylase inhibitors
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4950
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Lahtela-Kakkonen, Maija and Nikolić, Katarina and Ganesan, A.",
year = "2018",
journal = "Epigenetic Chemical Biology – Action CM1406, Computational Methods in Drug Design. Training School 22 – 24 March 2018, Istanbul, Turkey",
title = "Computer-aided design of histone deacetylase inhibitors",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4950"
}

Ružić, D., Đoković, N., Petković, M., Agbaba, D., Lahtela-Kakkonen, M., Nikolić, K.,& Ganesan, A.. (2018). Computer-aided design of histone deacetylase inhibitors. in Epigenetic Chemical Biology – Action CM1406, Computational Methods in Drug Design. Training School 22 – 24 March 2018, Istanbul, Turkey.
https://hdl.handle.net/21.15107/rcub_farfar_4950

Ružić D, Đoković N, Petković M, Agbaba D, Lahtela-Kakkonen M, Nikolić K, Ganesan A. Computer-aided design of histone deacetylase inhibitors. in Epigenetic Chemical Biology – Action CM1406, Computational Methods in Drug Design. Training School 22 – 24 March 2018, Istanbul, Turkey. 2018;.
https://hdl.handle.net/21.15107/rcub_farfar_4950 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Lahtela-Kakkonen, Maija, Nikolić, Katarina, Ganesan, A., "Computer-aided design of histone deacetylase inhibitors" in Epigenetic Chemical Biology – Action CM1406, Computational Methods in Drug Design. Training School 22 – 24 March 2018, Istanbul, Turkey (2018),
https://hdl.handle.net/21.15107/rcub_farfar_4950 .

TY  - CONF
AU  - Nikolić, Katarina
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Lahtela-Kakkonen, Maija
AU  - Ganesan, A.
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4929
AB  - The concept of gene expression is continuously explained with epigenetic modification. Post-translational histone acetylation and DNA methylation are dominant epigenetic alterations of the genome. Histone deacetylases (HDAC) play essential role in this process and therefore are very intensively investigated drug targets. The alteration in the structure and function of HDAC isoforms are identified in the pathogenesis of inflammation, cancer, and neurodegeneration. Eleven human HDAC isoforms are sharing a highly conserved catalytic domain. Among them, HDAC6 and SIRT2 are important for a wide range of diseases, due to their unique physiological functions. In our research, we have applied pharmacophore modelling, virtual screening, molecular docking and molecular dynamic methodologies for design and identification of selective HDAC6 and SIRT2 inhibitors. Recently resolved the crystal structure of catalytic domain II of human HDAC6 discovered a wide binding site essential for the substrate recognition. We have successfully used these structural features of human HDAC6 catalytic domain II to rationally design selective HDAC6 inhibitors. Newly published X-ray structures of selective ligand-SIRT2 complexes have revealed high conformational flexibility of this enzyme, and gave us more details about mechanism of action of sirtuin 2 inhibitors. Based on these findings we have performed molecular dynamic study of SIRT2 and tried to explain the conformational changes during enzyme catalysis. Since small number of selective HDAC modulators have been reported so far, rational design of HDAC6 and SIRT2 inhibitors are essential for further progress in discovery of epigenetic drugs.
PB  - iMedPub LTD
C3  - Journal of organic & inorganic chemistry
T1  - Computer-aided drug design of selective histone deacetylase inhibitors
SP  - 28
EP  - 28
DO  - 10.21767/2472-1123-C2-005
ER  - 

@conference{
author = "Nikolić, Katarina and Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Lahtela-Kakkonen, Maija and Ganesan, A.",
year = "2018",
abstract = "The concept of gene expression is continuously explained with epigenetic modification. Post-translational histone acetylation and DNA methylation are dominant epigenetic alterations of the genome. Histone deacetylases (HDAC) play essential role in this process and therefore are very intensively investigated drug targets. The alteration in the structure and function of HDAC isoforms are identified in the pathogenesis of inflammation, cancer, and neurodegeneration. Eleven human HDAC isoforms are sharing a highly conserved catalytic domain. Among them, HDAC6 and SIRT2 are important for a wide range of diseases, due to their unique physiological functions. In our research, we have applied pharmacophore modelling, virtual screening, molecular docking and molecular dynamic methodologies for design and identification of selective HDAC6 and SIRT2 inhibitors. Recently resolved the crystal structure of catalytic domain II of human HDAC6 discovered a wide binding site essential for the substrate recognition. We have successfully used these structural features of human HDAC6 catalytic domain II to rationally design selective HDAC6 inhibitors. Newly published X-ray structures of selective ligand-SIRT2 complexes have revealed high conformational flexibility of this enzyme, and gave us more details about mechanism of action of sirtuin 2 inhibitors. Based on these findings we have performed molecular dynamic study of SIRT2 and tried to explain the conformational changes during enzyme catalysis. Since small number of selective HDAC modulators have been reported so far, rational design of HDAC6 and SIRT2 inhibitors are essential for further progress in discovery of epigenetic drugs.",
publisher = "iMedPub LTD",
journal = "Journal of organic & inorganic chemistry",
title = "Computer-aided drug design of selective histone deacetylase inhibitors",
pages = "28-28",
doi = "10.21767/2472-1123-C2-005"
}

Nikolić, K., Ružić, D., Đoković, N., Petković, M., Agbaba, D., Lahtela-Kakkonen, M.,& Ganesan, A.. (2018). Computer-aided drug design of selective histone deacetylase inhibitors. in Journal of organic & inorganic chemistry
iMedPub LTD., 28-28.
https://doi.org/10.21767/2472-1123-C2-005

Nikolić K, Ružić D, Đoković N, Petković M, Agbaba D, Lahtela-Kakkonen M, Ganesan A. Computer-aided drug design of selective histone deacetylase inhibitors. in Journal of organic & inorganic chemistry. 2018;:28-28.
doi:10.21767/2472-1123-C2-005 .

Nikolić, Katarina, Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Lahtela-Kakkonen, Maija, Ganesan, A., "Computer-aided drug design of selective histone deacetylase inhibitors" in Journal of organic & inorganic chemistry (2018):28-28,
https://doi.org/10.21767/2472-1123-C2-005 . .

TY  - CONF
AU  - Ružić, Dušan
AU  - Đoković, Nemanja
AU  - Petković, Miloš
AU  - Agbaba, Danica
AU  - Lahtela-Kakkonen, Maija
AU  - Ganesan A, A.
AU  - Nikolić, Katarina
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4924
AB  - The concept of gene expression is continuously explained with epigenetic modifications. One of the most studied enzymes which have an influence on histone posttranslational modifications are histone deacetylases (HDACs). The overexpression and alterations in the structure of HDACs isoforms are described in the pathogenesis of cancer, inflammation and neurodegeneration. With different cellular function and tissue distribution of HDACs, scientists introduced them as attractive targets used in novel drug discovery protocols.
Rational drug design of novel small molecules is usually guided by computational approaches. In our laboratory, we use ligand-based (pharmacophore modeling and virtual screening) and structure-based (molecular docking and molecular dynamics) drug design methodologies. The main focus in our drug design project is identification of selective HDAC6 and SIRT2 inhibitors. With respect to all published data, very small number of selective HDAC modulators has been reported so far. Here, we present rational design of novel selective HDAC6 and SIRT2 inhibitors as promising drug candidates for further development and structure optimization.
PB  - Society of Physical Chemists of Serbia
C3  - Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry, 24-28 September, 2018, Belgrade, Serbia
T1  - Rational design of selective histone deacetylase inhibitors
VL  - II
SP  - 923
EP  - 929
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4924
ER  - 

@conference{
author = "Ružić, Dušan and Đoković, Nemanja and Petković, Miloš and Agbaba, Danica and Lahtela-Kakkonen, Maija and Ganesan A, A. and Nikolić, Katarina",
year = "2018",
abstract = "The concept of gene expression is continuously explained with epigenetic modifications. One of the most studied enzymes which have an influence on histone posttranslational modifications are histone deacetylases (HDACs). The overexpression and alterations in the structure of HDACs isoforms are described in the pathogenesis of cancer, inflammation and neurodegeneration. With different cellular function and tissue distribution of HDACs, scientists introduced them as attractive targets used in novel drug discovery protocols.
Rational drug design of novel small molecules is usually guided by computational approaches. In our laboratory, we use ligand-based (pharmacophore modeling and virtual screening) and structure-based (molecular docking and molecular dynamics) drug design methodologies. The main focus in our drug design project is identification of selective HDAC6 and SIRT2 inhibitors. With respect to all published data, very small number of selective HDAC modulators has been reported so far. Here, we present rational design of novel selective HDAC6 and SIRT2 inhibitors as promising drug candidates for further development and structure optimization.",
publisher = "Society of Physical Chemists of Serbia",
journal = "Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry, 24-28 September, 2018, Belgrade, Serbia",
title = "Rational design of selective histone deacetylase inhibitors",
volume = "II",
pages = "923-929",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4924"
}

Ružić, D., Đoković, N., Petković, M., Agbaba, D., Lahtela-Kakkonen, M., Ganesan A, A.,& Nikolić, K.. (2018). Rational design of selective histone deacetylase inhibitors. in Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry, 24-28 September, 2018, Belgrade, Serbia
Society of Physical Chemists of Serbia., II, 923-929.
https://hdl.handle.net/21.15107/rcub_farfar_4924

Ružić D, Đoković N, Petković M, Agbaba D, Lahtela-Kakkonen M, Ganesan A A, Nikolić K. Rational design of selective histone deacetylase inhibitors. in Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry, 24-28 September, 2018, Belgrade, Serbia. 2018;II:923-929.
https://hdl.handle.net/21.15107/rcub_farfar_4924 .

Ružić, Dušan, Đoković, Nemanja, Petković, Miloš, Agbaba, Danica, Lahtela-Kakkonen, Maija, Ganesan A, A., Nikolić, Katarina, "Rational design of selective histone deacetylase inhibitors" in Physical Chemistry 2018 (Proceedings) 14th International Conference on Fundamental and Applied Aspects of Physical Chemistry, 24-28 September, 2018, Belgrade, Serbia, II (2018):923-929,
https://hdl.handle.net/21.15107/rcub_farfar_4924 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Nikolić, Katarina
AU  - Lahtela‐Kakkonen, Maija
AU  - Agbaba, Danica
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4893
AB  - Sirtuins are highly conserved class of NAD+-dependent lysine deacetylases. Altered function of sirtuin 2 (Sirt2)
is related to pathogenesis of cancer, inflammation and neurodegeneration, which makes Sirt2 very attractive drug
target in novel epigenetic research [1]. A number of Sirt2 inhibitors have been recently developed, but for most
of them are missing structural information of their interaction with the enzyme [2, 3]. Our molecular dynamic
(MD) study was performed on recently resolved crystal structures of selective ligand-Sirt2 complexes [1]. In the
MD study were defined significant interactions with novel inhibitors, one of key residues responsible for
conformational stability of cofactor-binding pocket, and residue acting as gate-keeper for cofactor-binding loop.
Some residues completely changed orientation after the MD simulation, compared to the starting crystal
structures. This result indicates on the errors in the X-ray structures that may have influence on structure-based
design of novel inhibitors. After clustering of MD trajectory, 20 conformations (centroids) from 20 clusters of
Sirt2 have been selected as representative conformations for retrospective structure based virtual screening. The
virtual screening performances were significantly improved by use of the ensemble of conformations, selected
with this MD methodology, compared to screening against available X-ray structures.
PB  - Section for Medicinal Chemistry of the Slovenian Pharmaceutical Society
C3  - EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract
T1  - Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors
SP  - 305
EP  - 305
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4893
ER  - 

@conference{
author = "Đoković, Nemanja and Nikolić, Katarina and Lahtela‐Kakkonen, Maija and Agbaba, Danica",
year = "2018",
abstract = "Sirtuins are highly conserved class of NAD+-dependent lysine deacetylases. Altered function of sirtuin 2 (Sirt2)
is related to pathogenesis of cancer, inflammation and neurodegeneration, which makes Sirt2 very attractive drug
target in novel epigenetic research [1]. A number of Sirt2 inhibitors have been recently developed, but for most
of them are missing structural information of their interaction with the enzyme [2, 3]. Our molecular dynamic
(MD) study was performed on recently resolved crystal structures of selective ligand-Sirt2 complexes [1]. In the
MD study were defined significant interactions with novel inhibitors, one of key residues responsible for
conformational stability of cofactor-binding pocket, and residue acting as gate-keeper for cofactor-binding loop.
Some residues completely changed orientation after the MD simulation, compared to the starting crystal
structures. This result indicates on the errors in the X-ray structures that may have influence on structure-based
design of novel inhibitors. After clustering of MD trajectory, 20 conformations (centroids) from 20 clusters of
Sirt2 have been selected as representative conformations for retrospective structure based virtual screening. The
virtual screening performances were significantly improved by use of the ensemble of conformations, selected
with this MD methodology, compared to screening against available X-ray structures.",
publisher = "Section for Medicinal Chemistry of the Slovenian Pharmaceutical Society",
journal = "EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract",
title = "Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors",
pages = "305-305",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4893"
}

Đoković, N., Nikolić, K., Lahtela‐Kakkonen, M.,& Agbaba, D.. (2018). Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors. in EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract
Section for Medicinal Chemistry of the Slovenian Pharmaceutical Society., 305-305.
https://hdl.handle.net/21.15107/rcub_farfar_4893

Đoković N, Nikolić K, Lahtela‐Kakkonen M, Agbaba D. Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors. in EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract. 2018;:305-305.
https://hdl.handle.net/21.15107/rcub_farfar_4893 .

Đoković, Nemanja, Nikolić, Katarina, Lahtela‐Kakkonen, Maija, Agbaba, Danica, "Combined molecular dynamics and virtual screening studies to identify novel sirtuin 2 inhibitors" in EFMC-ISMC, XXV EFMC International Symposium on Medicinal Chemistry, Book of Abstract (2018):305-305,
https://hdl.handle.net/21.15107/rcub_farfar_4893 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
AU  - Lahtela‐Kakkonen, Maija
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4885
AB  - Modulacija aktivnosti epigenetičkog brisača, NAD‐zavisne protein deacetilaze
sirtuina 2 (SIRT2), poslednjih godina se pokazala kao obećavajuća strategija u lečenju
Parkinsonove bolesti, depresije, određenih tipova kancera, ishemijsko‐reperfuzionih
povreda itd. Nasuprot terapijskom potencijalu, još uvek nijedan predstavnik ove grupe
farmakološki aktivnih supstanci nije našao svoje mesto na tržištu. Najčešći problemi sa
dosada opisanim SIRT2 inhibitorima predstavljaju niska potentnost, loša selektivnost,
kao i loše farmakokinetičke osobine što dalje opravdava razvoj novih predstavnika.
Cilj ovog rada je bio ispitivanje konformacionih promena SIRT2 u prisustvu
inhibitora i dalje poboljšanje dostupnih kristalografskih modela u cilju razvoja
efikasnijeg protokola virtual screening‐a.
Polazeći od 5 različitih kristalografskih struktura SIRT2‐inhibitor kompleksa,
ukupno 1,5 μs simulacija molekulske dinamike u eksplicitnom solventu je izvedeno. 3D
deskriptori zasnovani na GRID‐u i linearna diskriminantna analiza su korišćeni za
virtual screening (VS) studiju.
Konformaciona fleksibilnost SIRT2‐inhibitor kompleksa zabeležena tokom
simulacija ukazuje na značajnu fleksibilnost aktivnog mesta i posledično na multiple
vezivne modove inhibitora. Nakon procedure klasterovanja trajektorije, nekoliko
relevantnih modela kompleksa je izdvojeno i uključeno u dalju VS studiju. VS modeli
generisani pomoću tri relevantna kompleksa dobijena studijom molekulske dinamike
su pokazali značajno bolje performanse u poređenju sa modelima dobijenim pomoću do
danas opisanih kristalografskih struktura. Performanse generisanog VS protokola su
značajno poboljšane i u odnosu na do danas publikovane protokole. Rezultati ove
studije jasno ukazuju na značaj uračunavanja fleksibilnosti aktivnog mesta u racionalni
dizajn SIRT2 inhibitora. Novi hemotipovi potenijalnih inhibitora SIRT2 su izdvojeni iz
baza komercijalno dostupnih jedinjenja primenom generisanih VS modela.
U ovoj studiji formirani su realističniji modeli aktivnog mesta sirtuina 2 kojima
su značajno poboljšane performanse virtual screening‐a u odnosu na do danas
publikovane studije. Rezultati ove studije, uključujući i opisane konformacione
promene doprinose sveobuhvatnom razumevanju odnosa strukture i aktivnosti SIRT2
inhibitora i dodatno racionalizuju dizajn selektivnijih i potentnijih inhibitora.
AB  - Modulation of activity of epigenetic eraser, NAD‐dependent protein deacetylase
sirtuin 2 (SIRT2), recently emerged as promising therapeutic strategy for the treatment
of many diseases, including Parkinson’s disease, depression, some types of cancers,
necrotic injuries (ischemic stroke, myocardial infarction) etc. Contrary to therapeutic
potential, none of SIRT2 inhibitors reported to date has been approved for the market.
Some of the most common problems with current SIRT2 inhibitors include poor
potency, selectivity and pharmacokinetic properties which justify further development
of novel inhibitors.
The Aim of this study was to explore conformational space of sirtuin2‐inhibitor
complexes and further refinement of available crystallographic structures in order to
develop more efficient virtual screening (VS) protocol.
Starting from five different crystallographic structures of SIRT2 co‐crystalized
with inhibitors, total of 1.5 μs of molecular dynamics (MD) simulations in explicit
solvent has been performed. GRID‐based 3D descriptors and linear discriminant
analysis were used for virtual screening.
Significant conformational flexibility of SIRT2‐inhibitor complexes was observed
during simulations indicating overall binding site flexibility and multiple binding modes
of inhibitors. Several atomistic models of SIRT2‐inhibitor complexes were extracted
and used for structure‐based VS study. VS models generated from three extracted
SIRT2‐inhibitor complexes were significantly better compared to VS models generated
from available crystallographic structures. Generated VS protocol was also better in
performance compared to published virtual screening studies. These results clearly
indicate importance of considering flexibility of binding site in rational design of SIRT2
inhibitors. Obtained models were used for screening of commercial databases of
compounds. Several chemotypes of potential novel SIRT2 inhibitors have been
identified.
Refined atomistic models of SIRT2‐inhibitor complexes have been generated and
significant improvement of virtual screening performance has been achieved. These
results further rationalize design of SIRT2 inhibitors with improved selectivity and
potency.
PB  - Savez farmaceutskih udruženja Srbije (SFUS)
C3  - Arhiv za farmaciju
T1  - Simulacije molekulske dinamike i virtual screening studija inhibitora sirtuina 2
T1  - Molecular dynamics‐based virtual screening of sirtuin 2 inhibitors
VL  - 68
IS  - 2
SP  - 338
EP  - 339
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4885
ER  - 

@conference{
author = "Đoković, Nemanja and Nikolić, Katarina and Agbaba, Danica and Lahtela‐Kakkonen, Maija",
year = "2018",
abstract = "Modulacija aktivnosti epigenetičkog brisača, NAD‐zavisne protein deacetilaze
sirtuina 2 (SIRT2), poslednjih godina se pokazala kao obećavajuća strategija u lečenju
Parkinsonove bolesti, depresije, određenih tipova kancera, ishemijsko‐reperfuzionih
povreda itd. Nasuprot terapijskom potencijalu, još uvek nijedan predstavnik ove grupe
farmakološki aktivnih supstanci nije našao svoje mesto na tržištu. Najčešći problemi sa
dosada opisanim SIRT2 inhibitorima predstavljaju niska potentnost, loša selektivnost,
kao i loše farmakokinetičke osobine što dalje opravdava razvoj novih predstavnika.
Cilj ovog rada je bio ispitivanje konformacionih promena SIRT2 u prisustvu
inhibitora i dalje poboljšanje dostupnih kristalografskih modela u cilju razvoja
efikasnijeg protokola virtual screening‐a.
Polazeći od 5 različitih kristalografskih struktura SIRT2‐inhibitor kompleksa,
ukupno 1,5 μs simulacija molekulske dinamike u eksplicitnom solventu je izvedeno. 3D
deskriptori zasnovani na GRID‐u i linearna diskriminantna analiza su korišćeni za
virtual screening (VS) studiju.
Konformaciona fleksibilnost SIRT2‐inhibitor kompleksa zabeležena tokom
simulacija ukazuje na značajnu fleksibilnost aktivnog mesta i posledično na multiple
vezivne modove inhibitora. Nakon procedure klasterovanja trajektorije, nekoliko
relevantnih modela kompleksa je izdvojeno i uključeno u dalju VS studiju. VS modeli
generisani pomoću tri relevantna kompleksa dobijena studijom molekulske dinamike
su pokazali značajno bolje performanse u poređenju sa modelima dobijenim pomoću do
danas opisanih kristalografskih struktura. Performanse generisanog VS protokola su
značajno poboljšane i u odnosu na do danas publikovane protokole. Rezultati ove
studije jasno ukazuju na značaj uračunavanja fleksibilnosti aktivnog mesta u racionalni
dizajn SIRT2 inhibitora. Novi hemotipovi potenijalnih inhibitora SIRT2 su izdvojeni iz
baza komercijalno dostupnih jedinjenja primenom generisanih VS modela.
U ovoj studiji formirani su realističniji modeli aktivnog mesta sirtuina 2 kojima
su značajno poboljšane performanse virtual screening‐a u odnosu na do danas
publikovane studije. Rezultati ove studije, uključujući i opisane konformacione
promene doprinose sveobuhvatnom razumevanju odnosa strukture i aktivnosti SIRT2
inhibitora i dodatno racionalizuju dizajn selektivnijih i potentnijih inhibitora., Modulation of activity of epigenetic eraser, NAD‐dependent protein deacetylase
sirtuin 2 (SIRT2), recently emerged as promising therapeutic strategy for the treatment
of many diseases, including Parkinson’s disease, depression, some types of cancers,
necrotic injuries (ischemic stroke, myocardial infarction) etc. Contrary to therapeutic
potential, none of SIRT2 inhibitors reported to date has been approved for the market.
Some of the most common problems with current SIRT2 inhibitors include poor
potency, selectivity and pharmacokinetic properties which justify further development
of novel inhibitors.
The Aim of this study was to explore conformational space of sirtuin2‐inhibitor
complexes and further refinement of available crystallographic structures in order to
develop more efficient virtual screening (VS) protocol.
Starting from five different crystallographic structures of SIRT2 co‐crystalized
with inhibitors, total of 1.5 μs of molecular dynamics (MD) simulations in explicit
solvent has been performed. GRID‐based 3D descriptors and linear discriminant
analysis were used for virtual screening.
Significant conformational flexibility of SIRT2‐inhibitor complexes was observed
during simulations indicating overall binding site flexibility and multiple binding modes
of inhibitors. Several atomistic models of SIRT2‐inhibitor complexes were extracted
and used for structure‐based VS study. VS models generated from three extracted
SIRT2‐inhibitor complexes were significantly better compared to VS models generated
from available crystallographic structures. Generated VS protocol was also better in
performance compared to published virtual screening studies. These results clearly
indicate importance of considering flexibility of binding site in rational design of SIRT2
inhibitors. Obtained models were used for screening of commercial databases of
compounds. Several chemotypes of potential novel SIRT2 inhibitors have been
identified.
Refined atomistic models of SIRT2‐inhibitor complexes have been generated and
significant improvement of virtual screening performance has been achieved. These
results further rationalize design of SIRT2 inhibitors with improved selectivity and
potency.",
publisher = "Savez farmaceutskih udruženja Srbije (SFUS)",
journal = "Arhiv za farmaciju",
title = "Simulacije molekulske dinamike i virtual screening studija inhibitora sirtuina 2, Molecular dynamics‐based virtual screening of sirtuin 2 inhibitors",
volume = "68",
number = "2",
pages = "338-339",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4885"
}

Đoković, N., Nikolić, K., Agbaba, D.,& Lahtela‐Kakkonen, M.. (2018). Simulacije molekulske dinamike i virtual screening studija inhibitora sirtuina 2. in Arhiv za farmaciju
Savez farmaceutskih udruženja Srbije (SFUS)., 68(2), 338-339.
https://hdl.handle.net/21.15107/rcub_farfar_4885

Đoković N, Nikolić K, Agbaba D, Lahtela‐Kakkonen M. Simulacije molekulske dinamike i virtual screening studija inhibitora sirtuina 2. in Arhiv za farmaciju. 2018;68(2):338-339.
https://hdl.handle.net/21.15107/rcub_farfar_4885 .

Đoković, Nemanja, Nikolić, Katarina, Agbaba, Danica, Lahtela‐Kakkonen, Maija, "Simulacije molekulske dinamike i virtual screening studija inhibitora sirtuina 2" in Arhiv za farmaciju, 68, no. 2 (2018):338-339,
https://hdl.handle.net/21.15107/rcub_farfar_4885 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Nikolić, Katarina
AU  - Lahtela‐Kakkonen, Maija
AU  - Agbaba, Danica
PY  - 2018
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/4871
PB  - Cancéropôle Grand Ouest  3 Chaussée de la Madeleine  44000 NANTES
C3  - EpiNantes 2018 meeting, 16th –17th October, 2018 NANTES, France
T1  - Identification of potential sirtuin2 inhibitors through molecular dynamics simulations, virtual screening and binding free-energy analysis
UR  - https://hdl.handle.net/21.15107/rcub_farfar_4871
ER  - 

@conference{
author = "Đoković, Nemanja and Nikolić, Katarina and Lahtela‐Kakkonen, Maija and Agbaba, Danica",
year = "2018",
publisher = "Cancéropôle Grand Ouest  3 Chaussée de la Madeleine  44000 NANTES",
journal = "EpiNantes 2018 meeting, 16th –17th October, 2018 NANTES, France",
title = "Identification of potential sirtuin2 inhibitors through molecular dynamics simulations, virtual screening and binding free-energy analysis",
url = "https://hdl.handle.net/21.15107/rcub_farfar_4871"
}

Đoković, N., Nikolić, K., Lahtela‐Kakkonen, M.,& Agbaba, D.. (2018). Identification of potential sirtuin2 inhibitors through molecular dynamics simulations, virtual screening and binding free-energy analysis. in EpiNantes 2018 meeting, 16th –17th October, 2018 NANTES, France
Cancéropôle Grand Ouest  3 Chaussée de la Madeleine  44000 NANTES..
https://hdl.handle.net/21.15107/rcub_farfar_4871

Đoković N, Nikolić K, Lahtela‐Kakkonen M, Agbaba D. Identification of potential sirtuin2 inhibitors through molecular dynamics simulations, virtual screening and binding free-energy analysis. in EpiNantes 2018 meeting, 16th –17th October, 2018 NANTES, France. 2018;.
https://hdl.handle.net/21.15107/rcub_farfar_4871 .

Đoković, Nemanja, Nikolić, Katarina, Lahtela‐Kakkonen, Maija, Agbaba, Danica, "Identification of potential sirtuin2 inhibitors through molecular dynamics simulations, virtual screening and binding free-energy analysis" in EpiNantes 2018 meeting, 16th –17th October, 2018 NANTES, France (2018),
https://hdl.handle.net/21.15107/rcub_farfar_4871 .

TY  - CONF
AU  - Đoković, Nemanja
AU  - Tyni, Jonna
AU  - Nikolić, Katarina
AU  - Agbaba, Danica
AU  - Lahtela-Kakkonen, Maija
PY  - 2017
UR  - https://farfar.pharmacy.bg.ac.rs/handle/123456789/5404
AB  - Sirtuin 2 (Sirt2) se poslednjih godina sve više povezuje sa patogenezom kancera,
neurodegeneracijom i inflamacijom zbog čega predstavlja atraktivan target za razvoj novih lekova.
Većina do danas okarakterisanih inhibitora Sirt2 ne poseduje odgovarajuću aktivnost i/ili
selektivnost. Kristalografske strukture objavljene u poslednjih par godina obezbedile su određeni
pomak u razvoju novih inhibitora, međutim i dalje postoje nedoumice u vezi sa mehanizmom
inhibicije koje su posledica visoke konformacone fleksibilnosti Sirt2 enzima. U cilju sticanja
detaljnijeg uvida u konformacionu fleksibilnost Sirt2, izvedeno je sedamnaest simulacija
molekulske dinamike u trajanju od po 100ns. Rezultati ove studije ukazali su na neke od ključnih
rezidua neophodnih za stabilizaciju kompleksa Sirt2/inhibitor. Takođe, opisane konformacije daju
jasniji uvid u katalitički ciklus deacilovanja. Opisan je i značaj konformacije kofaktorske petlje na
konformaciju vezivnog mesta inhibitora. Rezultati ove studije će omogućiti racionalniji pristup
dizajnu selektivnijih i potentnijih inhibitora sirtuina2.
AB  - Sirtuin 2 (Sirt2) has been implicated in pathogenesis of cancer, inflammation and neurodegeneration,
which makes Sirt2 attractive target for development of novel therapeutics. A number of small
molecule Sirt2 inhibitors have been reported, but most of them lack selectivity and/or high potency.
Very recently published X-ray structures of selective ligand/Sirt2 complexes have revealed more
details about mechanism of action of inhibitors, but some information still missing. Here, we will
try to answer on questions regarding the conformational changes during enzyme catalysis, based on
our recent molecular dynamic study of Sirt2. Total of seventeen 100 ns simulations have been
performed on five different crystal structures. Results of this study have suggested one of key
residues responsible for conformational stability of cofactor-binding loop and significant interaction
with novel inhibitors. Further, “closing” of Sirt2 induced by presence of substrate has been described
as major factor responsible for conformational changes in substrate-binding site. In conclusion, this
study provides dynamic information on Sirt2 and may facilitate the rational design on novel, more
potent and selective inhibitors.
PB  - Srpsko hemijsko društvo, Beograd
C3  - 54. Savetovanje Srpskog hemijskog društva. 5. Konferencija mladih hemičara Srbije. Kratki izvodi, Septembar 29 i 30, 2017, Beograd, Srbija
T1  - Ipitivanje konformacionih promena sirtuina 2 primenom simulacija
molekulske dinamike
T1  - Exploring conformational changes of sirtuin 2- molecular
dynamic approach
SP  - 93
EP  - 93
UR  - https://hdl.handle.net/21.15107/rcub_farfar_5404
ER  - 

@conference{
author = "Đoković, Nemanja and Tyni, Jonna and Nikolić, Katarina and Agbaba, Danica and Lahtela-Kakkonen, Maija",
year = "2017",
abstract = "Sirtuin 2 (Sirt2) se poslednjih godina sve više povezuje sa patogenezom kancera,
neurodegeneracijom i inflamacijom zbog čega predstavlja atraktivan target za razvoj novih lekova.
Većina do danas okarakterisanih inhibitora Sirt2 ne poseduje odgovarajuću aktivnost i/ili
selektivnost. Kristalografske strukture objavljene u poslednjih par godina obezbedile su određeni
pomak u razvoju novih inhibitora, međutim i dalje postoje nedoumice u vezi sa mehanizmom
inhibicije koje su posledica visoke konformacone fleksibilnosti Sirt2 enzima. U cilju sticanja
detaljnijeg uvida u konformacionu fleksibilnost Sirt2, izvedeno je sedamnaest simulacija
molekulske dinamike u trajanju od po 100ns. Rezultati ove studije ukazali su na neke od ključnih
rezidua neophodnih za stabilizaciju kompleksa Sirt2/inhibitor. Takođe, opisane konformacije daju
jasniji uvid u katalitički ciklus deacilovanja. Opisan je i značaj konformacije kofaktorske petlje na
konformaciju vezivnog mesta inhibitora. Rezultati ove studije će omogućiti racionalniji pristup
dizajnu selektivnijih i potentnijih inhibitora sirtuina2., Sirtuin 2 (Sirt2) has been implicated in pathogenesis of cancer, inflammation and neurodegeneration,
which makes Sirt2 attractive target for development of novel therapeutics. A number of small
molecule Sirt2 inhibitors have been reported, but most of them lack selectivity and/or high potency.
Very recently published X-ray structures of selective ligand/Sirt2 complexes have revealed more
details about mechanism of action of inhibitors, but some information still missing. Here, we will
try to answer on questions regarding the conformational changes during enzyme catalysis, based on
our recent molecular dynamic study of Sirt2. Total of seventeen 100 ns simulations have been
performed on five different crystal structures. Results of this study have suggested one of key
residues responsible for conformational stability of cofactor-binding loop and significant interaction
with novel inhibitors. Further, “closing” of Sirt2 induced by presence of substrate has been described
as major factor responsible for conformational changes in substrate-binding site. In conclusion, this
study provides dynamic information on Sirt2 and may facilitate the rational design on novel, more
potent and selective inhibitors.",
publisher = "Srpsko hemijsko društvo, Beograd",
journal = "54. Savetovanje Srpskog hemijskog društva. 5. Konferencija mladih hemičara Srbije. Kratki izvodi, Septembar 29 i 30, 2017, Beograd, Srbija",
title = "Ipitivanje konformacionih promena sirtuina 2 primenom simulacija
molekulske dinamike, Exploring conformational changes of sirtuin 2- molecular
dynamic approach",
pages = "93-93",
url = "https://hdl.handle.net/21.15107/rcub_farfar_5404"
}

Đoković, N., Tyni, J., Nikolić, K., Agbaba, D.,& Lahtela-Kakkonen, M.. (2017). Ipitivanje konformacionih promena sirtuina 2 primenom simulacija
molekulske dinamike. in 54. Savetovanje Srpskog hemijskog društva. 5. Konferencija mladih hemičara Srbije. Kratki izvodi, Septembar 29 i 30, 2017, Beograd, Srbija
Srpsko hemijsko društvo, Beograd., 93-93.
https://hdl.handle.net/21.15107/rcub_farfar_5404

Đoković N, Tyni J, Nikolić K, Agbaba D, Lahtela-Kakkonen M. Ipitivanje konformacionih promena sirtuina 2 primenom simulacija
molekulske dinamike. in 54. Savetovanje Srpskog hemijskog društva. 5. Konferencija mladih hemičara Srbije. Kratki izvodi, Septembar 29 i 30, 2017, Beograd, Srbija. 2017;:93-93.
https://hdl.handle.net/21.15107/rcub_farfar_5404 .

Đoković, Nemanja, Tyni, Jonna, Nikolić, Katarina, Agbaba, Danica, Lahtela-Kakkonen, Maija, "Ipitivanje konformacionih promena sirtuina 2 primenom simulacija
molekulske dinamike" in 54. Savetovanje Srpskog hemijskog društva. 5. Konferencija mladih hemičara Srbije. Kratki izvodi, Septembar 29 i 30, 2017, Beograd, Srbija (2017):93-93,
https://hdl.handle.net/21.15107/rcub_farfar_5404 .