title: A Mechanism-Based Model for the Prediction of the Metabolic Sites of Steroids Mediated by Cytochrome P450 3A4.
abstract: Early prediction of xenobiotic metabolism is essential for drug discovery and development. As the most important human drug-metabolizing enzyme, cytochrome P450 3A4 has a large active cavity and metabolizes a broad spectrum of substrates. The poor substrate specificity of CYP3A4 makes it a huge challenge to predict the metabolic site(s) on its substrates. This study aimed to develop a mechanism-based prediction model based on two key parameters, including the binding conformation and the reaction activity of ligands, which could reveal the process of real metabolic reaction(s) and the site(s) of modification. The newly established model was applied to predict the metabolic site(s) of steroids; a class of CYP3A4-preferred substrates. 38 steroids and 12 non-steroids were randomly divided into training and test sets. Two major metabolic reactions, including aliphatic hydroxylation and N-dealkylation, were involved in this study. At least one of the top three predicted metabolic sites was validated by the experimental data. The overall accuracy for the training and test were 82.14% and 86.36%, respectively. In summary, a mechanism-based prediction model was established for the first time, which could be used to predict the metabolic site(s) of CYP3A4 on steroids with high predictive accuracy.
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. daiziru@dicp.ac.cn.|Graduate School of Chinese Academy of Sciences, Beijing 100049, China. daiziru@dicp.ac.cn.
authors.forename: Zi-Ru
authors.initials: ZR
authors.lastname: Dai
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. aicy@dicp.ac.cn.
authors.forename: Chun-Zhi
authors.initials: CZ
authors.lastname: Ai
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. geguangbo@dicp.ac.cn.
authors.forename: Guang-Bo
authors.initials: GB
authors.lastname: Ge
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. hyqjeff@outlook.com.
authors.forename: Yu-Qi
authors.initials: YQ
authors.lastname: He
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. wjj@dicp.ac.cn.
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Wu
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. wangjy@dicp.ac.cn.
authors.forename: Jia-Yue
authors.initials: JY
authors.lastname: Wang
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. dldxmanhuizi@163.com.
authors.forename: Hui-Zi
authors.initials: HZ
authors.lastname: Man
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. jiayan@dicp.ac.cn.|Graduate School of Chinese Academy of Sciences, Beijing 100049, China. jiayan@dicp.ac.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jia
authors.affiliation: Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China. ylingdicp@gmail.com.
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry* / Q000378:metabolism; D062105:Molecular Docking Simulation; D008969:Molecular Sequence Data; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D013256:Steroids / Q000737:chemistry* / Q000494:pharmacology; D013379:Substrate Specificity
chemical_list: D013256:Steroids; D051544:Cytochrome P-450 CYP3A
keywords: CYP3A4; activation energy; mechanism-based prediction; metabolic site; steroids