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

蛋白-蛋白相互作用涉及多种生理过程. 其中HIF-VHL作为局部缺血性心脏病的重要靶标得到了学术界和工业界的广泛关注. 本文使用分子动力学模拟和结合自由能计算研究pro-like的小分子抑制剂对VHL-HIF的抑制机理. Pro-like抑制剂能够与HIF竞争性地结合在VHL蛋白上，从而破坏VHL-HIF相互作用. 基于抑制机理给出了pro-like抑制剂的优化策略.

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 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.