【摘要】 p53-MDM2相互作用的抑制已经成为治疗癌症的新方法.本文将分子动力学模拟和MM-PBSA(molecular mechanics/passion-Boltzman surface area)方法结合起来研究MDM2-p53相互作用机制。结果证明范德华相互作用驱动了MDM2与p53的结合.基于残基-残基相互作用的计算不仅证明p53的三个残基Phe19′,Trp23′和Leu26′与MDM2有较强的相互作用,而且还发现另外两个残基Leu22′和Pro27′也与MDM2有较强的相互作用,这为抗癌药物的设计提供了新靶标.同时也证明CH-CH,CH-π和π-π相互作用驱动了p53在MDM2疏水性裂缝中的结合.更多还原

【Abstract】 Inhibition of the MDM2-p53 interaction is considered to be a new therapeutic strategy to activate wild-type p53 in tumors.Molecular dynamics(MD) simulations followed by molecular mechanics/ passion-Boltzman surface area(MM-PBSA) analyses were used to study mechanism of the p53-MDM2 interaction.Results show that van der Waals energy is the dominant factor of the p53-MDM2 interaction. Calculations based on residue-residue interaction not only suggest that three residues Phe19’, Trp23’ and Leu26’ of p53 take part in strong interaction with MDM2,but additional two residues Leu22’ and Pro27’ also interact strongly with MDM2,This result provides new targets for the designs of the p53-MDM2 interaction inhibitors.At the same time,our studies suggest that CH-CH,CH-πandπ-πinteractions drive the binding of p53 to MDM2.We expect that this study can contribute significantly to the designs of the potent inhibitors targeting the p53-MDM2 interaction.更多还原