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Using a homology model of cytochrome P450 2D6 to predict substrate site of metabolism

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Abstract

CYP2D6 is an important enzyme that is involved in first pass metabolism and is responsible for metabolizing ~25% of currently marketed drugs. A homology model of CYP2D6 was built using X-ray structures of ligand-bound CYP2C5 complexes as templates. This homology model was used in docking studies to rationalize and predict the site of metabolism of known CYP2D6 substrates. While the homology model was generally found to be in good agreement with the recently solved apo (ligand-free) X-ray structure of CYP2D6, significant differences between the structures were observed in the B′ and F–G helical region. These structural differences are similar to those observed between ligand-free and ligand-bound structures of other CYPs and suggest that these conformational changes result from induced-fit adaptations upon ligand binding. By docking to the homology model using Glide, it was possible to identify the correct site of metabolism for a set of 16 CYP2D6 substrates 85% of the time when the 5 top scoring poses were examined. On the other hand, docking to the apo CYP2D6 X-ray structure led to a loss in accuracy in predicting the sites of metabolism for many of the CYP2D6 substrates considered in this study. These results demonstrate the importance of describing substrate-induced conformational changes that occur upon binding. The best results were obtained using Glide SP with van der Waals scaling set to 0.8 for both the receptor and ligand atoms. A discussion of putative binding modes that explain the distribution of metabolic sites for substrates, as well as a relationship between the number of metabolic sites and substrate size, are also presented. In addition, analysis of these binding modes enabled us to rationalize the typical hydroxylation and O-demethylation reactions catalyzed by CYP2D6 as well as the less common N-dealkylation.

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Acknowledgments

The authors thank Yuchen Bai from the Wyeth Bioinformatics Department for his help with sequence analysis of CYP2D6 polymorphs and Will Somers for support of this work.

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  1. Rayomand J. Unwalla

    Present address: Pfizer Research, 445 Eastern Point Road, Groton, CT, 06340, USA

  2. Jason B. Cross

    Present address: Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, MA, 02421, USA

  3. Sumeet Salaniwal

    Present address: Accelrys, Inc., 10188 Telesis Court, San Diego, CA, 92129, USA

Authors and Affiliations

  1. Chemical Sciences, Wyeth Research, S-2421, 500 Arcola Road, Collegeville, PA, 19426, USA

    Rayomand J. Unwalla, Jason B. Cross & Sumeet Salaniwal

  2. Drug Safety and Metabolism, Wyeth Research, 500 Arcola Road, Collegeville, PA, 19426, USA

    Adam D. Shilling, Louis Leung & John Kao

  3. Chemical Sciences, Wyeth Research, 865 Ridge Road, Princeton, NJ, 08543, USA

    Christine Humblet

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Correspondence to Rayomand J. Unwalla.

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Rayomand J. Unwalla and Jason B. Cross contributed equally to this work.

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Unwalla, R.J., Cross, J.B., Salaniwal, S. et al. Using a homology model of cytochrome P450 2D6 to predict substrate site of metabolism. J Comput Aided Mol Des 24, 237–256 (2010). https://doi.org/10.1007/s10822-010-9336-6

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