title: Synthesis, evaluation and molecular modeling of cyclic tetrapeptide histone deacetylase inhibitors as anticancer agents.
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.
authors.affiliation: School of Life Science and Biotechnology, Dalian University of Technology, Dalian 116024, China.
authors.forename: Dawei
authors.initials: D
authors.lastname: Huang
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Li
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.forename: Zhilong
authors.initials: Z
authors.lastname: Xiu
authors.forename: Norikazu
authors.initials: N
authors.lastname: Nishino
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry; D056572:Histone Deacetylase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006655:Histone Deacetylases / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D056004:Molecular Dynamics Simulation; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D013816:Thermodynamics; D015032:Zinc / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D056572:Histone Deacetylase Inhibitors; D010456:Peptides, Cyclic; D006655:Histone Deacetylases; D015032:Zinc