Inhibition Mechanism of Hydroxyproline-like Small Inhibitors to Disorder HIF-VHL Interaction by Molecular Dynamic Simulations and Binding Free Energy Calculations
Chinese Journal of Chemical Physics(2021)
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 stronger binding affinity toward VHL. Binding free energy calculations and free energy decompositions suggested that the modification of various regions of pro-like inhibitor may provide useful information for future drug design.
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关键词
Von Hippel Lindau, Hypoxia-inducible factor, Inhibitor, Molecular dynamics simulation, Binding free energy
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