Laboratory of Molecular Modeling and Design, State Kay Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Science, 116011 China.
J Mol Graph Model. 2011 Sep;30:46-53. doi: 10.1016/j.jmgm.2011.06.003. Epub 2011 Jun 13.
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 generalized Born surface area (MM-GBSA) analyses were used to study the inhibitory mechanisms of four small molecule inhibitors, K23, YIN, DIZ and IMZ on the p53-MDM2 interaction. We found excellent agreement between the rank of the calculated absolute binding free energies using the MM-GBSA method and the experimentally determined rank. The results show that van der Waals energy is the dominant factor for the binding of the four inhibitors. Statistical analyses of the hydrophobic contacts between the inhibitors and MDM2 were performed, and the results suggested that these inhibitors form stable hydrophobic interactions with six residues of MDM2: Leu54, Gly58, Ile61, Met62, Val93 and His96. Calculations of the detailed van der Waals interactions between non-peptide inhibitors and individual protein residues can provide insights into the inhibitor-protein binding mechanism. Our studies suggest that the CH-π and π-π interactions between the four inhibitors and protein residues drive binding of the inhibitors in the hydrophobic cleft of MDM2.
抑制 MDM2-p53 相互作用被认为是激活肿瘤中野生型 p53 的一种新的治疗策略。采用分子动力学（MD）模拟和分子力学广义 Born 表面面积（MM-GBSA）分析方法研究了四种小分子抑制剂 K23、YIN、DIZ 和 IMZ 对 p53-MDM2 相互作用的抑制机制。我们发现使用 MM-GBSA 方法计算的绝对结合自由能的计算排名与实验测定的排名之间具有极好的一致性。结果表明范德华能是四种抑制剂结合的主要因素。对抑制剂与 MDM2 之间的疏水接触进行了统计分析，结果表明这些抑制剂与 MDM2 的六个残基（Leu54、Gly58、Ile61、Met62、Val93 和 His96）形成稳定的疏水相互作用。计算非肽抑制剂与单个蛋白质残基之间的详细范德华相互作用可以深入了解抑制剂-蛋白质结合机制。我们的研究表明，四种抑制剂与蛋白质残基之间的 CH-π 和 π-π 相互作用驱动抑制剂在 MDM2 的疏水性裂缝中的结合。
