A Mechanism-Based Model for the Prediction of the Metabolic Sites of Steroids Mediated by Cytochrome P450 3A4

International Journal of Molecular Sciences

Zi-Ru Dai¹  Chun-Zhi Ai¹  Guang-Bo Ge¹  Yu-Qi He¹  Jing-Jing Wu¹  Jia-Yue Wang¹  Hui-Zi Man¹  Yan Jia¹  Ling Yang¹ 

[1] Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China; E-Mails:

关键词: CYP3A4;    steroids;    metabolic site;    mechanism-based prediction;    activation energy;   

DOI  :  10.3390/ijms160714677

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.