P38促细胞分裂蛋白酶活性抑制剂的分子对接及3D-QSAR研究(英文)

Docking and 3D-QSAR study on p38αMAP kinase inhibitors

运用分子对接方法研究了26个以嘧啶基咪唑环为基底的一系列同源化合物与p38促细胞分裂蛋白酶晶体结构的结合模式。采用比较分子力场分析法(CoMFA)对选取的对接优势构象进行三维定量构效关系(3D-QSAR)研究。建立了3D-QSAR的CoMFA模型,其非交叉验证系数r^2为0.986,交叉验证相关系数q^2为0.755,外部验证的标准偏差(SD为0.13,表明该模型合理、可信,并具有良好的预测能力。有趣的是,配体与活性周围氨基酸残基4个距离之和与其活性之间具有良好的线性关系(R^2=0.752),揭示了配体分子大小及与氨基酸残基结合的紧密程度对化合物的抑制活性起着主要的作用。最后,根据研究总结的规律设计了4个具有潜在高活性的嘧啶基咪唑衍生物。研究结果可为实验工作者合成新药提供理论有意义的理论参考。

A series of 26 pyridinylimidazole derivatives were docked to the X-ray structure of p38α MAP kinase, and their best docking conformations were analyzed by three-dimensional quantitative structure-activity relationship （3D-QSAR） studies. A robust 3D-QSAR model with high correlation coefficient （r2=0.986） and cross-validation coefficient （q2=0.755） has been established by comparative molecular field analysis （CoMFA）. An external validation by the compounds with high activities shows the standard deviation （SD） between experimental and predicted pIC50 values is 0.13. Docking results show that different binding modes of pyridinylimidazole derivatives have a great impact on the inhibitory activity of inhibitors. Interestingly, the summation of the four distances measuring the interaction between the ligands and the protein show a good linear relation （R2 = 0.752） with the inhibitory activity of the compounds. Finally, four new pyridinylimidazole derivatives with potent high p38α MAP kinase inhibitory activity have been theoretically designed.