QM/MM Modelling of Drug-Metabolizing Enzymes
Richard Lonsdale and Adrian J. Mulholland
Affiliation: Centre for Computational Chemistry, School of Chemistry, University of Bristol, Cantock’s Close, Bristol, BS8 1TS, UK.
Keywords: Cytochrome P450, drug metabolism, enzymes, epoxide hydrolase, modelling, quantum mechanics/molecular mechanics,
Making reliable predictions of drug metabolites requires detailed knowledge of the chemical reactivity of drug
metabolizing enzymes. Cytochrome P450 enzymes (P450s) play an important role in drug metabolism. Numerous adverse
drug reactions have been identified that occur as a result of interactions with P450s. These enzymes display complex reactivity
and the active oxidizing species is highly reactive and difficult to isolate, making P450s ideal candidates for computational
study. Hybrid quantum mechanics/molecular mechanics calculations (QM/MM) have provided valuable insight
into the reactivity of P450s, and will assist in the development of simpler predictive models. QM/MM methods have been
used to model the metabolism of several drug molecules in human P450s, and have successfully rationalized experimentally
observed selectivity. QM/MM calculations have been used to investigate the reactivity of other drug metabolizing
enzymes, such as soluble epoxide hydrolase and glutathione transferases. Here, we review the application of QM/MM
methods to modelling reactions catalyzed by drug metabolizing enzymes.
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