Comparative and pharmacophore model for deacetylase SIRT1.

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.