QM/MM modelling of drug-metabolizing enzymes

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 modeling reactions catalyzed by drug metabolizing enzymes. © 2014 Bentham Science Publishers.