目的 通过构建3D-定量构效关系（quantitative structure-activity relationship，QSAR）模型，研究黄酮类化合物对细胞色素P450酶1A1（cytochrome P450 1A1，CYP1A1）的抑制活性。方法 借助Topomer CoMFA方法开展黄酮类化合物结构-CYP1A1抑制活性构效关系研究；通过体外孵育体系对化合物CYP1A1抑制活性进行评价，开展预测模型验证和优化；通过分子对接技术探究黄酮类化合物抑制CYP1A1活性的作用机制。结果 构建的3D-QSAR模型交叉验证相关系数（q²）为0.800，非交互验证系数（r²）为0.965 0，外部验证的相关系数（r_pred²）为0.956 7，表现出良好的稳定性和预测能力。利用该模型预测9种黄酮类化合物的CYP1A1抑制活性，实验值与预测值的相关系数r²为0.832 8。分子对接结果显示，黄酮类化合物能与CYP1A1空腔内的THR497、ASN222、ASN255、SER116和ASP313等残基形成氢键，影响该类化合物的CYP1A1抑制活性大小。结论 构建的模型具有良好预测能力与稳定性，为设计高活性分子提供理论参考，为新型CYP1A1酶抑制剂的开发提供新的思路。

Objective To study the inhibitory activity of flavonoids on CYP1A1 enzyme by constructing a 3D-quantitative structure-activity relationship (3D-QSAR) model. Methods The structure-activity relationship between structure of flavonoids and inhibitory activity of CYP1A1 were observed by Topomer CoMFA method. The inhibitory activities of compounds were evaluated by using the incubation system in vitro, and the results were used for subsequent verification and optimization of the model. The action mechanism of flavonoids and CYP1A1 was studied by using molecular docking. Results The cross validation correlation coefficient (q²) of the obtained model was 0.800, the non-cross validation coefficient (r²) was 0.965 0, and the correlation coefficient (r_pred²) of the external validation was 0.956 7, suggesting that the model was robust and suitable for screening of CYP1A1 inhibitors. The model was used to predict the inhibitory activities of nine unreported flavonoids, and the results showed a good correlation coefficient between experimental and predicted values (r²=0.832 8). The results of molecular docking showed that small molecule compounds could form hydrogen bonds with amino acid residues THR497, ASN222, ASN255, SER116, and ASP313 in CYP1A1. This might be essential for the CYP1A1 inhibiting activities of flavonoids. Conclusion The model has good estimation ability and stability, which can provide theoretical reference for the design of high activity molecules and new ideas for the development of novel CYP1A1 enzyme inhibitors.

R285.51

国家自然科学基金优秀青年基金资助项目（81922070）；国家自然科学基金青年基金资助项目（82003850）；四川省大学生创新创业训练项目（S201910748117）