基于对接的植物激素3D-QSAR和分子动力学模拟

3D QSAR study of phytoestrogens:A combined molecular dockingand molecular dynamics simulation

采用分子对接和分子动力学(MD)模拟方法研究植物雌激素类化合物与雌激素受体的相互作用机制,对接结果表明,雌激素受体活性位点的疏水和氢键作用是影响植物雌激素化合物活性的主要原因,植物雌激素类化合物主要与氨基酸残基GLU353、ARG394、HIS524和LEU525之间形成氢键.然后以对接后的分子构象进行分子结构叠合,结合比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)方法建立了3D-QSAR模型.CoMFA模型的交叉验证相关系数(Q2)和非交叉验证相关系数(R2)值分别为0.676和0.994,标准估计误差SEE和F统计量分别为0.143和342.115;CoMSIA模型的Q2=0.565,R2=0.972,SEE=0.286和F=111.480.结果表明,CoMFA和CoMSIA模型具有良好的稳定性和预测能力,可为植物雌激素的雌激素效应研究提供有力的支持.采用MD模拟研究了小分子和受体蛋白的动力学情况,为对接结果的合理性提供了验证.

In this study,molecular docking and molecular dynamics（ MD） simulation approaches were adopted to study the interactions between phytoestrogens compounds and estrogen receptor. The docking results reveal that the estrogenic activity ofphytoestrogens compounds is mainly affected by the hydrophobic and H-bond interactions at the active site of estrogen receptor. There are several H-bonds between the phytoestrogens compounds mainly with amino acid residues GLU353,ARG394,HIS524,LEU525. Furthermore,two 3D-QSAR models were established based on the docking conformations using comparative molecular field analysis（ CoMFA） and comparative molecular similarity index analysis（ CoMSIA）. The statistic parameters of two models（ CoMFA model with a cross-validation Q2value of 0. 676 and a noncross-validation R2value of 0. 994,a standard errors value of 0.143 and F statistics value of 342.115 and CoMSIA model with Q2= 0.565,R2= 0. 972,SEE = 0. 286 and F = 111. 480） show that CoMFA and CoMSIA models have good stability and prediction ability. Finally,the dynamics between small molecules and protein are studied by the MD simulation,and the results provide a reasonable validation of docking results.