目的 应用三维定量构效关系（3D-QSAR）研究噻唑类衍生物结构的二氢乳清酸脱氢酶抑制活性，为该类药物的设计和筛选提供可靠的理论依据。方法 针对38个以噻唑为基本骨架的二氢乳清酸脱氢酶抑制剂，分别应用分子力场分析（CoMFA）和比较分子相似性指数分析（CoMSIA）2种经典的方法进行了三维定量构效关系（3D-QSAR）研究，建立相关模型，验证模型的预测能力，三维等势图分析噻唑类衍生物结构与活性的关系。结果 CoMFA模型的交叉验证系数q²为0.796，相关系数r²为0.978；CoMSIA模型的q²以及r²分别为0.721和0.976；2种模型对化合物的活性预测与实际值接近；三维等势图可以全面直观的分析化合物结构对其活性的影响。结论 该3D-QSAR模型三维等势图揭示了结构特征与抑制活性的关系，模型具有较好的预测能力和较强的稳定性，为进一步开发研究打下了较好的基础。

Objective The three-dimensional quantitative structure activity relationship (3D-QSAR) method was applied to study thiazole derivatives as potent inhibitors of dihydroorotate dehydrogenase, which provided useful guidance for more discovery of potent inhibitors of dihydroorotate dehydrogenase. Methods Molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to systematicly investigate 3D-QSAR of 38 hiazole derivatives as potent inhibitors of dihydroorotate dehydrogenase. Established models of CoMFA and CoMSIA and the predictive ability of models were validated. Three dimensional map was applied to analyzing the relationship between structure and activity of thiazole derivatives. Results The coefficients of cross validation q² and non-cross validation r² for CoMFA model were 0.796 and 0.978, and for CoMSIA model were 0.721 and 0.976 respectively. The prediction of activity of compound was close to the actual value of the two models. Effect of compound structure on its activity could be analyzed comprehensively and intuitively by three dimensional map. Conclusion The model reveals the relationship between the structure characteristics and the inhibitory activity, and has good predictive capability and stability to lay a good foundation for further development and research.

国家自然科学基金资助项目（81171508）；重庆市自然科学基金重点项目（CSTC2013JJB10004）