In Silico Investigation of Agonist Activity of a Structurally Diverse Set of Drugs to hPXR Using HM-BSM and HM-PNN  

作　　者：张一鸣 常美佳 杨旭曙 韩晓 

机构地区：[1]Schooiof Basic Medical Sciences,Nanjing Medical university,Nanjing 210029,China [2]School of Pharmacy,Nanjing Medical University,Nanjing 211166,China

出　　处：《Journal of Huazhong University of Science and Technology(Medical Sciences)》2016年第3期463-468,共6页华中科技大学学报（医学英德文版）

基　　金：supported by grants from the Natural Science Research Project of Institution of Higher Education of Jiangsu Province(No.11KJB180006);National Natural Science Foundation of China(No.21277074 and No.81302458)

摘　　要：The human pregnane X receptor（hPXR） plays a critical role in the metabolism, transport and clearance of xenobiotics in the liver and intestine. The hPXR can be activated by a structurally diverse of drugs to initiate clinically relevant drug-drug interactions. In this article, in silico investigation was performed on a structurally diverse set of drugs to identify critical structural features greatly related to their agonist activity towards h PXR. Heuristic method（HM）-Best Subset Modeling（BSM） and HM-Polynomial Neural Networks（PNN） were utilized to develop the linear and non-linear quantitative structure-activity relationship models. The applicability domain（AD） of the models was assessed by Williams plot. Statistically reliable models with good predictive power and explain were achieved（for HM-BSM, r^2=0.881, q^2_（LOO）=0.797, q^2_（EXT）=0.674; for HM-PNN, r^2=0.882, q^2_（LOO）=0.856, q^2_（EXT）=0.655）. The developed models indicated that molecular aromatic and electric property, molecular weight and complexity may govern agonist activity of a structurally diverse set of drugs to h PXR.The human pregnane X receptor（hPXR） plays a critical role in the metabolism, transport and clearance of xenobiotics in the liver and intestine. The hPXR can be activated by a structurally diverse of drugs to initiate clinically relevant drug-drug interactions. In this article, in silico investigation was performed on a structurally diverse set of drugs to identify critical structural features greatly related to their agonist activity towards h PXR. Heuristic method（HM）-Best Subset Modeling（BSM） and HM-Polynomial Neural Networks（PNN） were utilized to develop the linear and non-linear quantitative structure-activity relationship models. The applicability domain（AD） of the models was assessed by Williams plot. Statistically reliable models with good predictive power and explain were achieved（for HM-BSM, r^2=0.881, q^2_（LOO）=0.797, q^2_（EXT）=0.674; for HM-PNN, r^2=0.882, q^2_（LOO）=0.856, q^2_（EXT）=0.655）. The developed models indicated that molecular aromatic and electric property, molecular weight and complexity may govern agonist activity of a structurally diverse set of drugs to h PXR.

关 键 词：human pregnane X receptor agonist activity heuristic method-Best Subset Modeling heu ristic method-Polynomial Neural Networks structural features quantitative structure-activity relation ship 

分 类 号：R96[医药卫生—药理学]