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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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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Citation Formats

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.