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Development of a New Predictive Model for Interactions with Human Cytochrome P450 2A6 Using Pharmacophore Ensemble/Support Vector Machine (PhE/SVM) Approach

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Abstract

Purpose

The objective of this investigation was to yield a generalized in silico model to quantitatively predict CYP2A6-substrates/inhibitors interactions to facilitate drug discovery.

Methods

The newly invented pharmacophore ensemble/support vector machine (PhE/SVM) scheme was employed to generate the prediction model based on the data compiled from the literature.

Results

The predictions by the PhE/SVM model are in good agreement with the experimental observations for those molecules in the training set (n = 24, r 2 = 0.94, q 2 = 0.85, RMSE = 0.30) and the test set (n = 9, r 2 = 0.96, RMSE = 0.29). In addition, this in silico model performed equally well for those molecules in the external validation sets, namely one set of benzene and naphthalene derivatives (n = 45, r 2 = 0.81, RMSE = 0.46) and one set of amine neurotransmitters (n = 4, r 2 = 0.98, RMSE = 0.32). Furthermore, when compared with crystal structures, the calculated results are consistent with the published CYP2A6-substrate co-complex structure and the plasticity nature of CYP2A6 is also revealed.

Conclusions

This PhE/SVM model is an accurate and robust model and can be utilized for predicting interactions with CYP2A6, high-throughput screening and data mining to facilitate drug discovery.

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Abbreviations

AD:

Application domain

PhE:

Pharmacophore ensemble

SVM:

Support vector machine

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ACKNOWLEDGMENTS

This work was supported by the National Science Council, Taiwan. Parts of calculations were performed at the National Center for High-Performance Computing, Taiwan. The authors are grateful to Dr. G. H. Hakimelahi for reading the manuscript.

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  1. Department of Chemistry, National Dong Hwa University, Shoufeng, Hualien, 97401, Taiwan

    Max K. Leong, Yen-Ming Chen, Hong-Bin Chen & Po-Hong Chen

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Leong, M.K., Chen, YM., Chen, HB. et al. Development of a New Predictive Model for Interactions with Human Cytochrome P450 2A6 Using Pharmacophore Ensemble/Support Vector Machine (PhE/SVM) Approach. Pharm Res 26, 987–1000 (2009). https://doi.org/10.1007/s11095-008-9807-9

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