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

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 usi...

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Veröffentlicht in:Chinese journal of chemical physics 2021-12, Vol.34 (6), p.814-824
Hauptverfasser: Shi, Mingsong, Zhou, Xin, Cai, Yao, Li, Penghui, Qin, Dengxue, Yan, Xinrong, Du, Meng, Li, Shuo, Xu, Dingguo
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Sprache:eng
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Zusammenfassung: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.
ISSN:1674-0068
2327-2244
DOI:10.1063/1674-0068/cjcp2110198