Studies on the Molecular Mechanism between HDAC8 and Inhibitory in Different Bioactivities by Molecular Docking and MD Simulations

作     者：LIANG Zhen YAN Wen-Li LI Hong-Mei LI Ying ZHANG Rong LIANG Zhen;YAN Wen-Li;LI Hong-Mei;LI Ying;ZHANG Rong

作者机构：School of PharmacyGuangdong Pharmaceutical UniversityGuangzhou 510006China 

出 版 物：《Chinese Journal of Structural Chemistry》 (结构化学（英文）)

年 卷 期：2021年第40卷第10期

页      面：1298-1308页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 100705[医学-微生物与生化药学] 10[医学] 

基　　金：Talents Introduction Foundation for Universities of Guangdong Province(GD 2011) the Science and Technology Planning Project of Guangzhou(No.2013J4100071) 

主　　题：HDAC8 inhibitors molecular docking molecular dynamics(MD)simulations inhibition mechanism 

摘      要：HDAC8 is an important target for the treatment of many cancers and other diseases. To develop potent and selective HDAC8 inhibitors, molecular docking and molecular dynamics(MD) simulations were employed for investigation of the mechanism of HDAC8 inhibitions containing hydroxamic acid group. Compound 1 with high activity and compound 2 with low activity were selected for comparative study. Compound 1 formed a stronger chelation with Zn ion and was more stable in the HDAC8 pocket than compound 2. Residues HIS-180, ASP-178, ASP-267, and GLY-140 played a critical role in securing the position of compound 1. Both the head and tail of compound 1 formed strong hydrogen bonds with ASP-178, facilitating the ZBG of compound 1 close to the Zn ion so that they formed permanent chelation during the simulation period. The Cap group of the compounds with branch and long chains was advantageous to form interaction with active pocket opening. What’s more, based on the results of this study, three innovative recommendations for the design of highly active HDAC8 inhibitors were presented, which will be useful for the development of new HDAC8 inhibitors.