1 Biostructural Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet3 Department of Drug Design and Pharmacology, Faculty of Pharmaceutical Sciences, Københavns Universitet4 Biostructural Research, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, Københavns Universitet
INTRODUCTION: The cytochrome P450 enzymes (CYPs) metabolize many drug compounds. They catalyze a wide variety of reactions, and potentially, a large number of different metabolites can be generated. Density functional theory (DFT) has, over the past decade, been shown to be a powerful tool to rationalize and predict the possible metabolites generated by the CYPs as well as other drug-metabolizing enzymes. AREAS COVERED: We review applications of DFT on reactions performed by the CYPs and other drug-metabolizing enzymes able to perform oxidation reactions, with an emphasis on predicting which metabolites are produced. We also cover calculations of binding energies for complexes in which the ligands interact directly with the heme iron atom. EXPERT OPINION: DFT is a useful tool for prediction of the site of metabolism. The use of small models of the enzymes work surprisingly well for most CYP isoforms. This is probably due to the fact that the binding of the substrates is not the major determinant. When binding of the substrate plays a significant role, the well-known issue of determining the free energy of binding is the challenge. How approaches taking the protein environment into account, like docking, MD and QM/MM, can be used are discussed.
Expert Opinion on Drug Metabolism and Toxicology, 2014, Vol 10, Issue 2, p. 215-27