黄酮类化合物对细胞色素P450 CYP1A2的抑制作用及其构效关系研究  

Inhibition of human cytochrome P-450 CYP1A2 by flavonoids:a quantitative structure-activity relationship study

作　　者：李建康[1] 和凡[1] 毕惠嫦[1] 左中[2] 刘柏东[1] 罗海彬[1] 黄民[1] 

机构地区：[1]中山大学药学院,广东广州510080 [2]香港中文大学药剂学院,中国香港沙田

出　　处：《药学学报》2008年第12期1198-1204,共7页Acta Pharmaceutica Sinica

摘　　要：利用本实验室已建立的体外肝微粒体模型,测定36个黄酮类单体化合物对人细胞色素P450 CYP1A2的抑制活性,并使用三维定量构效关系方法研究化合物的分子结构参数与其抑制活性之间的关系。CoMSIA模型证实黄酮类化合物的结构参数与其CYP1A2抑制活性存在明显的相关性(模型的相关系数R2为0.948),且有良好的预测能力(交叉验证相关系数q2为0.630),同时使用"留五法"证实模型的稳定性和可靠性。结果表明,相对于黄酮,α-萘黄酮的π-π共轭体系更有利于提高化合物的抑制活性。根据获得的模型的三维等势图,在α-萘黄酮基础上,6、3′、4′位引入带正电基团或是疏水基团,同时5位引入带负电基团,能有效改善化合物的CYP1A2抑制活性。The inhibition activity of 36 flavonoids against CYP1A2 was determined by our previously developed in vitro method. The Comparative Molecular Similarity Indexes Analysis （CoMSIA） approach was used to probe the quantitative relationships between the flavonoids＇ molecular structural descriptors and their inhibitory activities. A reliable CoMSIA model with the combined electrostatic and hydrophobic fields was derived with the regression coefficient RE of 0. 948 and the cross-validation regression coefficient q^2 of 0. 630, separately, which is capable of elucidating the quantitative relationship between the 3D structural descriptors of the flavones and their bioactivities. Comparing with flavone, the larger π-π conjugated system of α-naphthoflavone significantly improved the biologically inhibitory ability. Based on the core structure of the latter, either electropositive substituents or hydrophobic groups at the 6, 3＇, and 4＇ ring positions or electronegative counterparts at the 5 ring position, can enhance the inhibitory potency against CYP1A2 according to the CoMSIA contour maps.

关 键 词：细胞色素P450 CYP1A2 抑制活性 黄酮类化合物 定量构效关系 药物设计 

分 类 号：R916.2[医药卫生—药学]