Inhibition mechanism of hydroxyproline-like small inhibitors to disorder HIF-VHL interaction by molecular dynamic simulations and binding free energy calculations

被引:1
作者
Shi, Mingsong [1 ]
Zhou, Xin [2 ]
Cai, Yao [2 ]
Li, Penghui [2 ]
Qin, Dengxue [2 ]
Yan, Xinrong [2 ]
Du, Meng [2 ]
Li, Shuo [2 ]
Xu, Dingguo [2 ,3 ]
机构
[1] Sichuan Univ, West China Hosp, State Key Lab Biotherapy, Chengdu 610041, Peoples R China
[2] Sichuan Univ, Coll Chem, Chengdu 610064, Peoples R China
[3] Sichuan Univ, Res Ctr Mat Genome Engn, Chengdu 610065, Peoples R China
基金
中国国家自然科学基金;
关键词
Von Hippel Lindau; Hypoxia-inducible factor; Inhibitor; Molecular dynamics simulation; Binding free energy; PROTEIN-PROTEIN INTERACTIONS; HYPOXIA-INDUCIBLE FACTOR; E3 UBIQUITIN LIGASE; ISCHEMIC-HEART-DISEASE; OPTIMIZATION; SURFACE; RECOGNITION; DERIVATIVES; STABILITY; DISCOVERY;
D O I
10.1063/1674-0068/cjcp2110198
中图分类号
O64 [物理化学(理论化学)、化学物理学]; O56 [分子物理学、原子物理学];
学科分类号
070203 ; 070304 ; 081704 ; 1406 ;
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.
引用
收藏
页码:814 / 824
页数:11
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