A computational analysis of the binding model of MDM2 with inhibitors.
A computational analysis of the binding model of MDM2 with inhibitors.
复制标题
MDM2 与抑制剂结合模型的计算分析
DOI：
10.1007/s10822-010-9366-0
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发表时间：
2010-08
影响因子：
3.5
通讯作者：
Zhang Q
中科院分区：
文献类型：
--
作者：
Hu G;Wang D;Liu X;Zhang Q
摘要：使用非肽小分子抑制剂阻断 MDM2-p53 相互作用是一种新的、有前景的抗癌药物设计策略。我们进行分子动力学模拟来研究一组六种非肽小分子抑制剂与 MDM2 的结合。使用分子力学泊松-玻尔兹曼表面积方法计算的相对结合自由能与实验确定的结果具有良好的相关性。研究表明，范德华能是每个复合物结合自由能的最大组成部分，这表明这些抑制剂对 MDM2 的亲和力主要由形状互补性决定。除了2,2-二甲基丁烷基团的构象外，A-配体和B-配体相同。量子力学和结合自由能计算也表明B配体是更可能的配体构象。计算抑制剂和单个蛋白质残基之间的详细结合自由能，通过解释模拟的结构和能量结果来深入了解抑制剂-蛋白质结合模型。研究表明，G1、G2和G3组模拟了p53中的Phe19、Trp23和Leu26残基及其与MDM2的相互作用，但G4组的结合模型与最初的模拟p53中Leu22残基的设计策略不同。图解摘要一组抑制剂的G1、G2和G3组模拟了Phe19、Trp23和Leu26 p53中的残基及其与MDM2的相互作用，但抑制剂8的G4组的结合模型与模拟p53中的Leu22残基的原始设计策略不同。
AbstractIt is a new and promising strategy for anticancer drug design to block the MDM2-p53 interaction using a non-peptide small-molecule inhibitor. We carry out molecular dynamics simulations to study the binding of a set of six non-peptide small-molecule inhibitors with the MDM2. The relative binding free energies calculated using molecular mechanics Poisson–Boltzmann surface area method produce a good correlation with experimentally determined results. The study shows that the van der Waals energies are the largest component of the binding free energy for each complex, which indicates that the affinities of these inhibitors for MDM2 are dominated by shape complementarity. The A-ligands and the B-ligands are the same except for the conformation of 2,2-dimethylbutane group. The quantum mechanics and the binding free energies calculation also show the B-ligands are the more possible conformation of ligands. Detailed binding free energies between inhibitors and individual protein residues are calculated to provide insights into the inhibitor-protein binding model through interpretation of the structural and energetic results from the simulations. The study shows that G1, G2 and G3 group mimic the Phe19, Trp23 and Leu26 residues in p53 and their interactions with MDM2, but the binding model of G4 group differs from the original design strategy to mimic Leu22 residue in p53.Graphical AbstractThe G1, G2 and G3 group of a group inhibitors mimic the Phe19, Trp23 and Leu26 residues in p53 and their interactions with MDM2, but the binding model of G4 group of inhibitor 8 differs from the original design strategy to mimic Leu22 residue in p53.
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