title: Comparative and pharmacophore model for deacetylase SIRT1.
abstract: Sirtuins are NAD-dependent histone deacetylases, which cleave the acetyl-group from acetylated proteins, such as histones but also the acetyl groups from several transcription factors, and in this way can change their activities. Of all seven mammalian SirTs, the human sirtuin SirT1 has been the most extensively studied. However, there is no crystal structure or comparative model reported for SirT1. We have therefore built up a three-dimensional comparison model of the SirT1 protein catalytic core (domain area from residues 244 to 498 of the full length SirT1) in order to assist in the investigation of active site-ligand interactions and in the design of novel SirT1 inhibitors. In this study we also propose the binding-mode of recently reported set of indole-based inhibitors in SirT1. The site of interaction and the ligand conformation were predicted by the use of molecular docking techniques. To distinguish between active and inactive compounds, a post-docking filter based on H-bond network was constructed. Docking results were used to investigate the pharmacophore and to identify a filter for database mining.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, Kuopio, FIN-70211, Finland. Tero.Huhtiniemi@uku.fi
authors.forename: Tero
authors.initials: T
authors.lastname: Huhtiniemi
authors.forename: Carsten
authors.initials: C
authors.lastname: Wittekindt
authors.forename: Tuomo
authors.initials: T
authors.lastname: Laitinen
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Antero
authors.initials: A
authors.lastname: Salminen
authors.forename: Antti
authors.initials: A
authors.lastname: Poso
authors.forename: Maija
authors.initials: M
authors.lastname: Lahtela-Kakkonen
mesh_terms: D000595:Amino Acid Sequence; D001426:Bacterial Proteins / Q000737:chemistry; D001665:Binding Sites; D019295:Computational Biology; D017124:Conserved Sequence; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007211:Indoles; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D056564:Sirtuin 1; D037761:Sirtuins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D015032:Zinc / Q000378:metabolism
chemical_list: D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D007211:Indoles; C030374:indole; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases; D015032:Zinc