Recent density functional theory model calculations of drug metabolism by cytochrome P450

Cytochrome P450 (P450) enzymes are the major catalysts involved in the oxidative metabolism of most drugs, steroids, carcinogens, and other chemicals. They catalyze a variety of reactions and convert chemicals to potentially reactive products as well as make compounds less toxic. More than 75% of drugs in clinical use are metabolized by P450s. Understanding the mechanism of drug metabolism by P450, in particular the chemical process, is indispensable in the early phases of drug discovery process. In this review, we discuss our recent theoretical studies on the mechanism of some specific compounds catalyzed by P450. Density functional theory (DFT) is used as the quantum mechanical (QM) tool to explore the fundamental mechanism of these reactions. These DFT calculations provide structures, energies, and some other properties of transition states and intermediates and thus shed light on the electronic factors that govern the stability and reactivity. These theoretical studies provide a complementary insight to experiment and suggest some new features. DFT serves a powerful tool to explore the chemical mechanism of drug metabolism by P450. The revealed fundamental mechanism concerning how the enzyme catalyzes the drug metabolism, especially the transition state of the rate-determining reaction step, could provide a valuable mechanistic base for rational design of novel drugs.