School of Science, Shandong Jiaotong University, Jinan, China.
CAS Key Laboratory of Receptor Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Chem Biol Drug Des. 2018 Oct;92(4):1763-1777. doi: 10.1111/cbdd.13345. Epub 2018 Jul 2.
Disruption of the p53-MDM2 interaction has been an efficient strategy to renew the function of wild-type p53. In this work, molecular dynamic simulations, molecular mechanics-generalized Born surface area method, and principal component analysis were combined to probe interaction mechanism of inhibitors 2TZ, 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2. The rank of our current predicted binding free energies is in agreement with that of the experimental values. The results demonstrate that the introductions of thiazole and pyridine rings into 2TZ as well as the change in the orientation of inhibitors lead to the increase in the polar interactions of 2U0, 2U1, 2U5, 2U6, and 2U7 with MDM2 relative to 2TZ. The information derived from principal component analysis suggests that inhibitor bindings produce significant effect on the binding cleft of MDM2 and make the binding cleft wider and bigger so as to accommodate different type inhibitors. This study is looked forward to contributing theoretical hints for designs of potent inhibitors targeting the p53-MDM2 interaction.
破坏 p53-MDM2 相互作用一直是恢复野生型 p53 功能的有效策略。在这项工作中，我们结合分子动力学模拟、分子力学-广义 Born 表面面积法和主成分分析，研究了抑制剂 2TZ、2U0、2U1、2U5、2U6 和 2U7 与 MDM2 的相互作用机制。我们目前预测的结合自由能的排序与实验值一致。结果表明，将噻唑和吡啶环引入 2TZ 以及抑制剂取向的改变导致 2U0、2U1、2U5、2U6 和 2U7 与 MDM2 的极性相互作用相对于 2TZ 增加。主成分分析得出的信息表明，抑制剂的结合对 MDM2 的结合裂隙产生了显著影响，使结合裂隙变宽变大，从而容纳不同类型的抑制剂。这项研究有望为设计针对 p53-MDM2 相互作用的有效抑制剂提供理论线索。
