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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

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2022
Novel_protocol_for_pub_2022.pdf (240.4Kb)
Authors
Đoković, Nemanja
Ružić, Dušan
Rahnasto‐Rilla, Minna
Srdić-Rajić, Tatjana
Lahtela‐Kakkonen, Maija
Nikolić, Katarina
Conference object (Published version)
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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 confor...mational 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 j...e 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.

Source:
Arhiv za farmaciju, 2022, 72, 4 suplement, S241-S242
Publisher:
  • Savez farmaceutskih udruženja Srbije (SFUS)
Funding / projects:
  • Ministry of Education, Science and Technological Development, Republic of Serbia, Grant no. 200161 (University of Belgrade, Faculty of Pharmacy) (RS-200161)
Note:
  • VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beograd

ISSN: 0004-1963

[ Google Scholar ]
Handle
https://hdl.handle.net/21.15107/rcub_farfar_4523
URI
https://farfar.pharmacy.bg.ac.rs/handle/123456789/4523
Collections
  • Radovi istraživača / Researchers’ publications
Institution/Community
Pharmacy
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 .

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