天然黄酮类化合物抑制CYP3A4的构效关系研究(英文)  

Inhibition of CYP3A4 by natural accurring flavonoids: A SAR and 3D-QSAR study

作　　者：汪巍[1,2] 李明[3] 艾纯芝[4] 杜艺玫 凌蕾 马菲菲[1,2] 周旭美[2] 鲁艳柳[1] 何芋岐[1,2] 

机构地区：[1]遵义医学院基础药理教育部重点实验室,贵州遵义563099 [2]遵义医学院药学院药学实验室,贵州遵义563099 [3]沈阳药科大学制药工程学院,辽宁沈阳110000 [4]中国科学院大连化学物理研究所生物技术部,辽宁大连116023

出　　处：《遵义医学院学报》2017年第1期6-16,共11页Journal of Zunyi Medical University

基　　金：国家自然科学基金资助项目(NO:81402985,81560673,81660685);上海市复方中药重点实验室(上海中医药大学)开放基金资助项目(NO:2014OP01);贵州省科学技术基金资助项目(NO:黔科合J字[2015]2158号,黔科合JZ字[2015]2010号);贵州省留学人员择优资助项目(NO:黔人项目资助合同[2015]03);遵义医学院博士科研启动基金资助项目(NO:F-736,F-744)

摘　　要：目的研究天然黄酮类化合物对CYP3A4的抑制活性并通过定性及三维定量分析两种方法挖掘天然黄酮结构中抑制CYP3A4活性的关键因素。方法利用睾酮特征代谢反应表征人肝微粒体中CYP3A4的活性。在此体系中,首先选取较高浓度初筛25种黄酮类化合物的抑制活性。对于抑制活性超过50%的化合物,进行多浓度测试以获得IC50值。最后分别采用定性和三维定量两种方式分析黄酮结构与CYP3A4抑制之间的相关性。结果初筛实验表明,黄酮苷元类化合物中的黄芩素、异鼠李素、山奈酚、白杨素、木犀草素、芹菜素、槲皮素、柚皮素以及豆蔻明9个化合物对CYP3A4表现出最强抑制作用。除了异鼠李素之外,另外8个化合物的抑制百分比高达90%。黄酮类化合物中主要是取代基的类型、羟基的数量和位置以及碳1、2位双键影响对CYP3A4的抑制活性。建立了预测性较好的反映黄酮结构及对CYP3A4抑制活性的定量计算模型。结论本文发现了黄酮类化合物抑制CYP3A4活性的关键结构特征,同时建立了可以用于黄酮类化合物抑制CYP3A4活性的计算化学模型。Objective Mining the key structure feature of natural occurring flavonoids for inhibition on CYP3A4 via SAR and 3D-QSAR strategy. Methods Evaluate the activity of CYP3A4 in human liver microsome incubation system via checking the specific probe reaction： 6β-hydroxylation of testosterone. Screen the inhibitory effect of 25 flavonoids at a relatively higher concentration. Check the IC50 values of flavonoids with inhibitory rate more than 50%. Using the tested and reported IC50 values to construct a 3D-QSAR model to predict the inhibitory potency of flavonoids other than the investigated 25 objects. Results Nine flavonoid glycones showed high inhibitory effect on CYP3A4. The number,type,and position of the substituted groups on flavonoid core structures are correlated with their inhibitory effect on CYP3A4. C1-C2 double bond promotes the inhibitory effect. A 3D-QSAR model was established and applied with good prediction. Conclusion Key structure features for CYP3A4 inhibition were extracted from flavonoids. A 3D-QSAR model for flavonoids related CYP3A4 inhibition prediction was established. Results of the present study would benefit the prediction of Food or Drug-Drug interaction mediated by flavonoids.

关 键 词：黄酮类化合物 CYP3A4 抑制 SAR 3D-QSAR 

分 类 号：R969.2[医药卫生—药理学]