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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,建立经典结构一活性关系(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。
OBJECTIVE: To establish a quantitative structure-activity relationship of novel diaryl-substituted -1,2,4-triazoles and to design a novel COX-2 inhibitor. Methods: The structures of 18 diaryl-1,2,4-triazole selective cyclooxygenase (COX-2) inhibitors were optimized by PM3 semiempirical quantum chemistry method. The data were searched for or calculated Using the step-by-step regression method, we established a 2D-QSAR. We used Autodock docking software to study the interaction of diaryl-1,2,4-triazoles and cyclooxygenase (COX- 2) docking, analysis of these compounds and cyclooxygenase in the three-dimensional structure of the complex and molecular docking free energy and inhibitory activity relationship. Results: The quantitative structure-activity relationship of COX-2 inhibitors with reasonable diaryl-substituted -1,2,4-triazoles showed that the activity of diaryl-substituted 1,2,4-triazoles Enzymes (COX-2) inhibitors have a stereostructure similar to tricyclic cyclooxygenase-2 inhibitors such as celecoxib, and the docking free energy has a good correlation with inhibitor activity. CONCLUSION: The model obtained can explain the existing structure-activity relationship and predict the ability of the same kind of compounds to guide the design of new inhibitors.