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论文类型：期刊论文

发表时间：2012-04-01

发表刊物：JOURNAL OF PEPTIDE SCIENCE

收录刊物：SCIE、PubMed、Scopus

卷号：18

期号：4

页面范围：242-251

ISSN号：1075-2617

关键字：histone deacetylase; histone deacetylase inhibitor; anticancer agent; cyclic tetrapeptide; docking; molecular dynamics

摘要：Histone deacetylase inhibitors (HDACIs) are a promising class of anticancer agents. To examine whether a slight change in the recognition domain could alter their inhibitory activity, we synthesized a series of cyclo(-l-Am7(S2Py)-Aib-l-Phe(n-Me)-d-Pro)derivatives and evaluated their HDAC inhibitory and anticancer activities. The peptides exhibited potent HDAC inhibitory activity and inhibited three human cancer cell lines with IC50 in the micromolar range. Docking and molecular dynamics simulation were conducted to explore the interaction mechanisms of class I and II HDACs with these inhibitors. It revealed that the zinc ion in the active site coordinated five atoms of HDACs and the sulfur atom of the inhibitor. The metal binding domains of these compounds interacted with HDAC2, and the surface recognition domains of these compounds interacted with HDAC4 through hydrogen bonding. The hydrophobic interactions also provided favorable contributions to stabilize the complexes. The results obtained from this study would be helpful for us to design some novel cyclic tetrapeptides that may act as potent HDACIs. Copyright (c) 2012 European Peptide Society and John Wiley & Sons, Ltd.