肿瘤蛋白MDMX与抑制剂PMI作用机制的分子动力学研究

Molecular Dynamics Insight into the Interaction Mechanism of Inhibitor PMI with MDMX

恢复抑癌蛋白p53的功能已经成为一种治疗癌症的新途径。本文采用分子动力学模拟和MM-PBSA方法计算了抑制剂PMI与肿瘤蛋白MDMX的结合自由能。结果表明范德华相互作用驱动了PMI与MDMX的结合。同时也使用基于残基对的自由能分解方法计算了残基–残基相互作用,结果不仅表明PMI的5个残基能与MDMX产生强烈的相互作用,而且也表明CH-CH,CH-π,π-π相互作用主导了PMI在MDMX疏水性裂缝中的结合。我们期望这个研究能为抑制p53-MDMX相互作用药物的研发提供理论上的启示。

Restoration of p53 function is considered to be a new therapeutic strategy for anti-cancers. Molecular Dynamics (MD) simulations coupled with Molecular Mechanics/Possion-Boltzman Surface Area (MM-PBSA) method were used to study the mechanism of the PMI-MDMX interaction. The results show that van der walls energy drives the PMI-MDMX interaction. Calculations based on residue-residue interaction were also performed, and the results not only suggest that five residues of PMI can produce strong interaction with MDMX, but also the CH-CH, CH-π, π-π interactions predominate the binding of PMI in the hydrophobic cleft of MDMX. We expect that this study can contribute significantly to the designs of the potent inhibitors inhibiting the PMI-MDMX interaction.