@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"
}