Determinants of Selectivity in Drug Metabolism by Cytochrome P450: QM/MM Modeling of Dextromethorphan Oxidation by CYP2D6

J Oláh, A.J Mulholland, J.N Harvey

Research output: Contribution to journalArticle (Academic Journal)peer-review

80 Citations (Scopus)
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Abstract

Cytochrome P450 enzymes play key roles in the metabolism of the majority of drugs. Improved models for prediction of likely metabolites will contribute to drug development. In this work, two possible metabolic routes (aromatic carbon oxidation and O-demethylation) of dextromethorphan are compared using molecular dynamics (MD) simulations and density functional theory (DFT). The DFTresults on a small active site model suggest that both reactions might occur competitively. Docking and MD studies of dextromethorphan in the active site of P450 2D6 show that the dextromethorphan is located close to heme oxygen in a geometry apparently consistent with competitive metabolism. In contrast, calculations of the reaction path in a large protein model [using a hybrid quantum mechanical–molecular mechanics (QM/MM) method] show a very strong preference for O-demethylation, in accordance with experimental results. The aromatic carbon oxidation reaction is predicted to have a high activation energy, due to the active site preventing formation of a favorable transition-state structure. Hence, the QM/MM calculations demonstrate a crucial role of many active site residues in determining reactivity of dextromethorphan in P450 2D6. Beyond substrate binding orientation and reactivity of Compound I, successful metabolite predictions must take into account the detailed mechanism of oxidation in the protein. These results demonstrate the potential of QM/MM methods to investigate specificity in drug metabolism.
Translated title of the contributionDeterminants of Selectivity in Drug Metabolism by Cytochrome P450: QM/MM Modeling of Dextromethorphan Oxidation by CYP2D6
Original languageEnglish
Pages (from-to)6050 - 6055
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number15
DOIs
Publication statusPublished - Mar 2011

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