Huhtiniemi Tero, Wittekindt Carsten, Laitinen Tuomo, Leppänen Jukka, Salminen Antero, Poso Antti, Lahtela-Kakkonen Maija
Department of Pharmaceutical Chemistry, University of Kuopio, P.O. Box 1627, Kuopio, FIN-70211, Finland.
J Comput Aided Mol Des. 2006 Sep;20(9):589-99. doi: 10.1007/s10822-006-9084-9. Epub 2006 Nov 11.
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.
沉默调节蛋白是依赖烟酰胺腺嘌呤二核苷酸（NAD）的组蛋白脱乙酰酶，它能从乙酰化蛋白（如组蛋白）上切割乙酰基，也能从几种转录因子上切割乙酰基，从而改变它们的活性。在所有七种哺乳动物沉默调节蛋白（SirTs）中，人类沉默调节蛋白SirT1的研究最为广泛。然而，目前尚未有关于SirT1的晶体结构或比较模型的报道。因此，我们构建了SirT1蛋白催化核心（全长SirT1第244至498位残基的结构域区域）的三维比较模型，以协助研究活性位点与配体的相互作用，并设计新型SirT1抑制剂。在本研究中，我们还提出了最近报道的一组基于吲哚的抑制剂在SirT1中的结合模式。通过分子对接技术预测了相互作用位点和配体构象。为了区分活性和非活性化合物，构建了基于氢键网络的对接后筛选方法。对接结果用于研究药效基团并确定数据库挖掘的筛选条件。
