title: An in silico approach to discovering novel inhibitors of human sirtuin type 2.
abstract: Type 2 human sirtuin (SIRT2) is a NAD(+)-dependent cytoplasmic protein that is colocalized with HDAC6 on microtubules. SIRT2 has been shown to deacetylate alpha-tubulin and to control mitotic exit in the cell cycle. To date, some small molecular inhibitors of SIRT2 have been identified; however, more inhibitors are still needed to improve the understanding of SIRT2 biological function and to discover its possible therapeutic indications. In this paper, an in silico identification procedure is described for discovering novel SIRT2 inhibitors. Molecular modeling and virtual screening were utilized to find potential compounds, which were then subjected to experimental tests for their SIRT2 inhibitory activity. Five of the 15 compounds tested in vitro showed inhibitory activity toward SIRT2, yielding a hit ratio of 33% in a micromolar level and thus demonstrating the usefulness of this procedure in finding new bioactive compounds. Two of the five compounds yielded in vitro IC(50) values of 56.7 and 74.3 microM, and these can be considered as novel inhibitors of SIRT2. On the basis of our results, a phenol moiety on the active compound is suggested to be important for SIRT2 inhibitory activity. This phenol group, together with a hydrophobic moiety and hydrogen-bonding features, is suggested to form an active SIRT2 pharmacophore.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, 70211 Kuopio, Finland. anu.tervo@csc.fi
authors.forename: Anu J
authors.initials: AJ
authors.lastname: Tervo
authors.forename: Sergiy
authors.initials: S
authors.lastname: Kyrylenko
authors.forename: Päivi
authors.initials: P
authors.lastname: Niskanen
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Tommi H
authors.initials: TH
authors.lastname: Nyrönen
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
mesh_terms: D000880:Anthraquinones / Q000737:chemistry; D001555:Benzene Derivatives / Q000737:chemistry; D001665:Binding Sites; D018360:Crystallography, X-Ray; D016208:Databases, Factual; D008958:Models, Molecular; D015394:Molecular Structure; D010636:Phenols / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry; D056565:Sirtuin 2; D037761:Sirtuins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D014230:Triazoles / Q000737:chemistry
chemical_list: D000880:Anthraquinones; D001555:Benzene Derivatives; D010636:Phenols; D011725:Pyridines; D014230:Triazoles; C474199:SIRT2 protein, human; D056565:Sirtuin 2; D037761:Sirtuins