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Pharmacophore modeling and virtual screening studies to identify novel selective SIRT2 inhibitors
Date
2019-06-01
Author
EREN, GÖKÇEN
Bruno, Agostino
Guntekin-Ergun, Sezen
Atalay, Rengül
Ozgencil, Fikriye
ÖZKAN, YEŞİM
Gozelle, Mahmut
Kaya, Selen Gozde
Costantino, Gabriele
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Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License
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Sirtuins (SIRTs) are a class of NAD(+)-dependent protein histone deacetylases (HDACs) that catalyse the reversible deacetylation of lysine residues in the histones or non-histone substrates. Mammalian sirtuins consist of seven isoforms (SIRT1-7), which show different subcellular localizations and enzymatic functions. Among the seven human sirtuins, SIRT2 predominantly located in the cytoplasm but is enriched in the nucleus during mitosis. Its activity has been found to be modulate the pathophysiology of various diseases such as cancer, metabolic and neurodegenerative disorders. Therefore, selective SIRT2 inhibitors are of growing interest as potentially candidate therapeutic agents to treat SIRT2-driven pathologies as well as valuable tools to investigate and define the biological roles of SIRT2. Herein, in order to identify potent leads against SIRT2, a multi-step pharmacophore based-virtual screening campaign was performed and 31 predicted compounds were subjected to in vitro biological evaluation. Finally, compound 2 and 3 showing better SIRT2 inhibition potency were selected for further in vitro cytotoxic assays against a panel of three human cancer cell lines. This study will hopefully provide a basis for developing potent and selective SIRT2 inhibitors.
Subject Keywords
Physical and Theoretical Chemistry
,
Spectroscopy
,
Materials Chemistry
,
Computer Graphics and Computer-Aided Design
URI
https://hdl.handle.net/11511/63048
Journal
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
DOI
https://doi.org/10.1016/j.jmgm.2019.02.014
Collections
Graduate School of Informatics, Article
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G. EREN et al., “Pharmacophore modeling and virtual screening studies to identify novel selective SIRT2 inhibitors,”
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
, pp. 60–73, 2019, Accessed: 00, 2020. [Online]. Available: https://hdl.handle.net/11511/63048.