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Article

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

by
Zi-Ru Dai
1,2,†,
Chun-Zhi Ai
1,†,
Guang-Bo Ge
1,
Yu-Qi He
1,
Jing-Jing Wu
1,
Jia-Yue Wang
1,
Hui-Zi Man
1,
Yan Jia
1,2 and
Ling Yang
1,*
1
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China
2
Graduate School of Chinese Academy of Sciences, Beijing 100049, China
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2015, 16(7), 14677-14694; https://doi.org/10.3390/ijms160714677
Submission received: 4 May 2015 / Revised: 26 May 2015 / Accepted: 27 May 2015 / Published: 30 June 2015
(This article belongs to the Section Biochemistry)
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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.
Keywords: CYP3A4; steroids; metabolic site; mechanism-based prediction; activation energy CYP3A4; steroids; metabolic site; mechanism-based prediction; activation energy

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MDPI and ACS Style

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. https://doi.org/10.3390/ijms160714677

AMA Style

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. International Journal of Molecular Sciences. 2015; 16(7):14677-14694. https://doi.org/10.3390/ijms160714677

Chicago/Turabian Style

Dai, Zi-Ru, Chun-Zhi Ai, Guang-Bo Ge, Yu-Qi He, Jing-Jing Wu, Jia-Yue Wang, Hui-Zi Man, Yan Jia, and Ling Yang. 2015. "A Mechanism-Based Model for the Prediction of the Metabolic Sites of Steroids Mediated by Cytochrome P450 3A4" International Journal of Molecular Sciences 16, no. 7: 14677-14694. https://doi.org/10.3390/ijms160714677

APA Style

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. (2015). A Mechanism-Based Model for the Prediction of the Metabolic Sites of Steroids Mediated by Cytochrome P450 3A4. International Journal of Molecular Sciences, 16(7), 14677-14694. https://doi.org/10.3390/ijms160714677

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