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Site of metabolism prediction on cytochrome P450 2C9: a knowledge-based docking approach

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Abstract

A novel structure-based approach for site of metabolism prediction has been developed. This knowledge-based method consists of three steps: (1) generation of possible metabolites, (2) docking the predicted metabolites to the CYP binding site and (3) selection of the most probable metabolites based on their complementarity to the binding site. As a proof of concept we evaluated our method by using MetabolExpert for metabolite generation and Glide for docking into the binding site of the CYP2C9 crystal structure. Our method could identify the correct metabolite among the three best-ranked compounds in 69% of the cases. The predictive power of our knowledge-based method was compared to that achieved by substrate docking and two alternative literature approaches.

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Acknowledgments

The authors would like to thank Márk Sándor for his useful comments.

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Authors and Affiliations

  1. Discovery Chemistry, Gedeon Richter plc, P.O. Box 27, 1475, Budapest, Hungary

    Ákos Tarcsay, Róbert Kiss & György M. Keserű

  2. Department of General and Analytical Chemistry, Budapest University of Technology and Economics, Szt. Gellért tér 4., 1111, Budapest, Hungary

    Ákos Tarcsay & György M. Keserű

Authors
  1. Ákos Tarcsay
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  2. Róbert Kiss
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  3. György M. Keserű
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Correspondence to György M. Keserű.

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Tarcsay, Á., Kiss, R. & Keserű, G.M. Site of metabolism prediction on cytochrome P450 2C9: a knowledge-based docking approach. J Comput Aided Mol Des 24, 399–408 (2010). https://doi.org/10.1007/s10822-010-9347-3

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  • DOI: https://doi.org/10.1007/s10822-010-9347-3

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