新型二芳基取代-1,2,4-三唑类化合物的抗炎构效关系和分子对接研究

目的:建立新型二芳基取代-1,2,4-三唑类化合物的定量构效关系,设计新型COX-2抑制剂.方法:采用PM3半经验量子化学法全优化18种二芳基取代-1,2,4-三唑类选择性环氧合酶(COX-2)抑制剂的结构,从数据中搜寻或计算它们的226种参数,利用逐步回归法,建立经典结构-活性关系(2D-QSAR);用Autodock对接软件研究二芳基取代-1,2,4-三唑类化合物与环氧合酶(COX-2)的对接,分析该类化合物与环氧合酶在复合物的立体结构以及分子对接自由能与抑制活性的关系.结果:建立合理二芳基取代-1,2,4-三唑类化合物COX-2抑制剂定量构效关系,表明活性二芳基取代-1,2,4-三唑类选择性环氧合酶(COX-2)抑制剂具有类似塞来昔布等三环类环氧合酶-2抑制剂的立体结构,并且对接自由能与抑制剂活性有较好的相关性.结论:所得的模型可以解释已有的构效关系,而且预测同类化合物能力较好,可指导设计新抑制剂.

QSAR and docking studies on a new series of diaryl-substituted-1,2,4-trizole derivatives COX-2 inhibitors

AIM:To disclose the quantitative structure-activity relationship of a new series of cyclooxygenase-2 inhibitors,diaryl-substi- tuted-1,2,4-trizole derivatives.Mtehods:The structures of inhibitors were optimized by PM3 semiempirieal quantum chemistry meth- ods,and the 2D-QSAR of inhibitors were studied by multiple regression method based on the structure parameters searched from data- base or theory calculation.These inhibitors docking with the active site in COX-2 were evaluated with Autodock method.Results:These studies produced good predictive 2D-QSAR model.It was found that the structures of diaryl-substituted -1,2,4-trizole derivatives COX- 2 inhibitors are similar to the structures of typical tricyclic cycloxygenase-2 selective inhibitors such as celecoxib,and the inhibitory ac- tivities log(l/C)are correlated with docking free energies. Conclusion:The QSAR can explains the dependence of COX-2 inhibiton upon the structures of diaryl-substituted-I ,2,4-trizole derivatives.Some structure information for design of new COX-2 inhibitors with higher activity has been given.