Pharmacophore modeling and virtual screening studies to identify novel selective SIRT2 inhibitors
| Autor: | Selen Gozde Kaya, Mahmut Gozelle, Gokcen Eren, Rengul Cetin-Atalay, Agostino Bruno, Sezen Guntekin-Ergun, Gabriele Costantino, Yeşim Özkan, Fikriye Ozgencil |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Models
Molecular Molecular Conformation Antineoplastic Agents SIRT2 Cell Line Structure-Activity Relationship 03 medical and health sciences Sirtuin 2 0302 clinical medicine Materials Chemistry Humans Computer Simulation Physical and Theoretical Chemistry Spectroscopy 030304 developmental biology chemistry.chemical_classification 0303 health sciences Virtual screening Dose-Response Relationship Drug Molecular Structure biology Computer Graphics and Computer-Aided Design Histone Deacetylase Inhibitors Histone Enzyme ROC Curve Biochemistry chemistry Acetylation 030220 oncology & carcinogenesis Sirtuin biology.protein NAD+ kinase Drug Screening Assays Antitumor Pharmacophore |
| Popis: | 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. (C) 2019 Elsevier Inc. All rights reserved. |
| Databáze: | OpenAIRE |
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