环氧合酶-2抑制剂的三维定量构效关系研究

Three Dimensional Quantitative Structure-activity Relationship of Cyclooxygenase-2 Inhibitors

建立三环系COX-1和COX-2抑制剂结构与活性的三维定量构效关系模型,为设计新型的具有选择性的COX-2抑制剂提供线索.通过与酶的对接并优化,确定化合物在受体结合腔中的构象,利用比较分子力场分析方法建立三维定量构效关系模型.模型1R_(cv)~2=0.685,最佳主成分数为6,传统相关系数为R^2=0.988,F=726.2,标准偏差S=0.080;模型2R_(cv)~2=0.573,最佳主成分数为6,传统相关系数为R^2=0.996,F=1147.6,标准偏差S=0.034.所得的模型不仅解释了化合物的构效关系,而且对预测集中的化合物有很好的预测能力;比较不同模型的系数相关图,分析了结构与活性、结构与选择性的关系,得到的结果可以指导新化合物的设计与合成.

To quantitatively disclose the relationship between activity and structure, selectivity and structure of a series of tricyclic COX-2 inhibitors, 62 COX-2 inhibitors and 36 COX-1 inhibitors were got from literatures as a training set with the aim of developing a 3D QSAR activity-structure model using CoMFA. The conformation was confirmed using dock program and its energy was minimized using the methods of 'Stp dese' and 'Conj grad' with the force field 'MMFF94' in the energy gradient convergence 0.21 kJ.mol(-1). Both of CoMFA models yield good statistical significance, with R-ev(2) = 0.685, R-2 = 0.988, F = 726.2, S = 0.080 in the model of COX structure and R-ev(2) = 0.573, R-2 = 0.996, F = 1147.6, S = 0.034 in the model of COX-1. The low deviations of cv calculated values from the measured ones indicate powerful predictive ability of the models. The 3D QSAR explains the dependence of activity upon the structures of the compounds. Some structural information for designing new COX-2 inhibitors with higher activity and selectivity has been given.