Inhibition Mechanism of Hydroxyproline-like Small Inhibitors to Disorder HIF-VHL Interaction by Molecular Dynamic Simulations and Binding Free Energy Calculations  

基于分子动力学和自由能计算研究小分子对HIF-VHL相互作用的抑制机理

作　　者：Mingsong Shi Xin Zhou Yao Cai Penghui Li Dengxue Qin Xinrong Yan Meng Du Shuo Li Dingguo Xu 石明松;周鑫;蔡瑶;李鹏辉;秦登雪;严新蓉;杜孟;李硕;徐定国(四川大学华西医院,生物治疗国家重点实验室,成都610041;四川大学化学学院,成都610064;四川大学材料基因工程研究中心,成都610065)

机构地区：[1]State Key Laboratory of Biotherapy,West China Hospital of Sichuan University,Chengdu 610041,China [2]College of Chemistry,Sichuan University,Chengdu 610064,China [3]Research Center for Material Genome Engineering,Sichuan University,Chengdu 610065,China

出　　处：《Chinese Journal of Chemical Physics》2021年第6期814-824,I0003,I0079-I0088,共22页化学物理学报（英文）

基　　金：supported by the National Natural Science Foundation of China(No.21973064);the Post-Doctor Research Project,West China Hospital,Sichuan University(No.2021HXBH017)。

摘　　要：Protein-protein interactions are vital for a wide range of biological processes.The interactions between the hypoxia-inducible factor and von Hippel Lindau(VHL)are attractive drug targets for ischemic heart disease.In order to disrupt this interaction,the strategy to target VHL binding site using a hydroxyproline-like(pro-like)small molecule has been reported.In this study,we focused on the inhibition mechanism between the pro-like inhibitors and the VHL protein,which were investigated via molecular dynamics simulations and binding free energy calculations.It was found that pro-like inhibitors showed a strong binding affinity toward VHL.Binding free energy calculations and free energy decompositions suggested that the modification of various regions of pro-like inhibitors may provide useful information for future drug design.

关 键 词：Von Hippel Lindau Hypoxia-inducible factor Inhibitor Molecular dynamics simulation Binding free energy 

分 类 号：TQ460.1[化学工程—制药化工]