Pharmacophore modeling and virtual screening studies to identify novel selective SIRT2 inhibitors

• Published in: Journal of molecular graphics & modelling 2019-06, Vol.89, p.60-73
• Main Authors: Eren, Gokcen, Bruno, Agostino, Guntekin-Ergun, Sezen, Cetin-Atalay, Rengul, Ozgencil, Fikriye, Ozkan, Yesim, Gozelle, Mahmut, Kaya, Selen Gozde, Costantino, Gabriele
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Cell Line; Computer Simulation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Humans; Models, Molecular; Molecular Conformation; Molecular Structure; MTT; Pharmacophore modeling; ROC Curve; SIRT2; Sirtuin; Sirtuin 2 - antagonists & inhibitors; Sirtuin 2 - chemistry; Structure-Activity Relationship; Virtual screening
• ISSN: 1093-3263; 1873-4243
• DOI: 10.1016/j.jmgm.2019.02.014

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. [Display omitted] •Multi-step pharmacophore based-virtual screening campaign was performed.•31 predicted compounds were subjected to in vitro biological evaluation.•Compound 2 and 3 were found to be effective on SIRT2 activity also exhibiting cell growth inhibition against different cancer cell lines.