Computational analysis of spiro-oxindole inhibitors of the MDM2-p53 interaction: insights and selection of novel inhibitors
Computational analysis of spiro-oxindole inhibitors of the MDM2-p53 interaction: insights and selection of novel inhibitors
复制标题
MDM2-p53 相互作用的螺羟吲哚抑制剂的计算分析：新型抑制剂的见解和选择
DOI：
10.1080/07391102.2015.1031178
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发表时间：
2016-01-01
影响因子：
4.4
通讯作者：
Peng, Cheng
中科院分区：
文献类型：
--
作者：
Huang, Wei;Cai, Lulu;Peng, Cheng
由于MDM 2是p53肿瘤抑制因子的抑制剂，因此破坏MDM 2-p53相互作用是癌症治疗的一种有前途的方法。在这里，我们使用分子动力学模拟，然后通过自由能分解分析，研究MDM 2的构象变化引起的三个已知的螺-羟吲哚抑制剂。个别能源条款的分析表明，货车范德华力和静电相互作用解释了这些抑制剂的结合亲和力。采用分子力学-广义Born表面积模型计算的3种抑制剂的结合自由能与实验数据一致，表明该方法的有效性.基于此结构-功能分析，选择了几种新的螺-羟吲哚衍生物，并评价了它们在体外阻断MDM 2-p53相互作用的能力。这些结果表明，结合计算机模拟和实验技术可以深入了解MDM 2抑制剂的结构-功能关系，并指导靶向MDM 2-p53相互作用的抗癌药物的合理设计。
Since MDM2 is an inhibitor of the p53 tumor suppressor, disrupting the MDM2-p53 interaction is a promising approach for cancer therapy. Here, we used molecular dynamics simulations followed by free energy decomposition analysis to study conformational changes in MDM2 induced by three known spiro-oxindole inhibitors. Analysis of individual energy terms suggests that van der Waals and electrostatic interactions explain much of the binding affinities of these inhibitors. Binding free energies calculated for the three inhibitors using the molecular mechanics-generalized Born surface area model were consistent with experimental data, suggesting the validity of this approach. Based on this structure-function analysis, several novel spiro-oxindole derivatives were selected and evaluated for their ability to block the MDM2-p53 interaction in vitro. These results suggest that combining in silico and experimental techniques can provide insights into the structure-function relationships of MDM2 inhibitors and guide the rational design of anticancer drugs targeting the MDM2-p53 interaction.