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

【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, r²=0.881, q²_LOO=0.797, q²_EXT=0.674; for HM-PNN, r²=0.882, q²_LOO=0.856, q²_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.更多还原

【Abstract】 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, r²=0.881, q²_LOO=0.797, q²_EXT=0.674; for HM-PNN, r²=0.882, q²_LOO=0.856, q²_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.更多还原