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抑制p53-MDM2相互作用已经成为癌症治疗的新途径.采用分子动力学模拟和MM-PBSA(molecular mechanics-Possion-Boltzmann surface area)方法研究了肽类抑制剂P4与MDM2的结合模式.研究表明P4与MDMD2疏水性裂缝的范德华作用是抑制剂结合的主导力量。采用丙氨酸变异计算研究了P4与MDM2的作用热区.结果表明残基Lys51,Leu54,Leu57,Ile61,Met62,Tyr67,Gln72,His73,Val93,His96和Ile99的丙氨酸变异导致了范德华作用的降低,而对极性相互作用几乎没有产生影响,同时也证明这些残基处于P4与MDM2作用表面的热区,对抑制剂的结合有重要贡献,这能为抗癌药物的设计提供理论上的指导.
Inhibition of p53-MDM2 interaction has become a new approach for the treatment of cancer.Molecular dynamics simulation and MM-PBSA (molecular mechanics-Possion-Boltzmann surface area) method was used to study the binding mode of peptide inhibitor P4 and MDM2. Van der Waal’s interaction with hydrophobic fractures of MDMD2 is the dominant force for inhibitor binding. The alanine variation of P4 and MDM2 was studied using alanine mutation calculation.The results showed that alanine variation of residues Lys51, Leu54, Leu57, Ile61, Met62, Tyr67, Gln72, His73, Val93, His96 and Ile99 resulted in van der Waals’ , And little or no effect on polar interactions. These residues are also found to be hot in the surface of the interaction between P4 and MDM2 and contribute significantly to the binding of inhibitors, which can theoretically provide the design of anti-cancer drugs Guidance.