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Indexed by:期刊论文

Date of Publication:2012-04-01

Journal:JOURNAL OF PEPTIDE SCIENCE

Included Journals:SCIE、PubMed、Scopus

Volume:18

Issue:4

Page Number:242-251

ISSN No.:1075-2617

Key Words:histone deacetylase; histone deacetylase inhibitor; anticancer agent; cyclic tetrapeptide; docking; molecular dynamics

Abstract: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.