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Int. J. Mol. Sci. 2015, 16(7), 14677-14694; doi:10.3390/ijms160714677

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

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
Graduate School of Chinese Academy of Sciences, Beijing 100049, China
These authors contributed equally to this work.
Author to whom correspondence should be addressed.
Academic Editor: ChulHee Kang
Received: 4 May 2015 / Revised: 26 May 2015 / Accepted: 27 May 2015 / Published: 30 June 2015
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
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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. View Full-Text
Keywords: CYP3A4; steroids; metabolic site; mechanism-based prediction; activation energy CYP3A4; steroids; metabolic site; mechanism-based prediction; activation energy

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Dai, Z.-R.; Ai, C.-Z.; Ge, G.-B.; He, Y.-Q.; Wu, J.-J.; Wang, J.-Y.; Man, H.-Z.; Jia, Y.; Yang, L. A Mechanism-Based Model for the Prediction of the Metabolic Sites of Steroids Mediated by Cytochrome P450 3A4. Int. J. Mol. Sci. 2015, 16, 14677-14694.

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