目的 應(yīng)用三維定量構(gòu)效關(guān)系（3D-QSAR）研究噻唑類衍生物結(jié)構(gòu)的二氫乳清酸脫氫酶抑制活性，為該類藥物的設(shè)計(jì)和篩選提供可靠的理論依據(jù)。方法 針對(duì)38個(gè)以噻唑?yàn)榛竟羌艿亩淙榍逅崦摎涿敢种苿?，分別應(yīng)用分子力場(chǎng)分析（CoMFA）和比較分子相似性指數(shù)分析（CoMSIA）2種經(jīng)典的方法進(jìn)行了三維定量構(gòu)效關(guān)系（3D-QSAR）研究，建立相關(guān)模型，驗(yàn)證模型的預(yù)測(cè)能力，三維等勢(shì)圖分析噻唑類衍生物結(jié)構(gòu)與活性的關(guān)系。結(jié)果 CoMFA模型的交叉驗(yàn)證系數(shù)q²為0.796，相關(guān)系數(shù)r²為0.978；CoMSIA模型的q²以及r²分別為0.721和0.976；2種模型對(duì)化合物的活性預(yù)測(cè)與實(shí)際值接近；三維等勢(shì)圖可以全面直觀的分析化合物結(jié)構(gòu)對(duì)其活性的影響。結(jié)論 該3D-QSAR模型三維等勢(shì)圖揭示了結(jié)構(gòu)特征與抑制活性的關(guān)系，模型具有較好的預(yù)測(cè)能力和較強(qiáng)的穩(wěn)定性，為進(jìn)一步開發(fā)研究打下了較好的基礎(chǔ)。

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.

國家自然科學(xué)基金資助項(xiàng)目（81171508）；重慶市自然科學(xué)基金重點(diǎn)項(xiàng)目（CSTC2013JJB10004）