Chapter 9. Drug Metabolism by Cytochrome P450: A Tale of Multistate Reactivity

Abstract

This chapter reviews the mechanism and function of cytochrome P450 enzymes as elucidated by computational approaches. Thus, the cytochromes P450 (CYP 450) are important heme enzymes in the human body, which metabolize about 80% of the 200 most commonly prescribed FDA approved drugs. The complexities that arise at the molecular level have driven the field of computational chemistry intensely and as a consequence many detailed theoretical studies into the mechanism and function of CYP 450 enzymes have been reported. These studies are reviewed here and it is shown what the basic reaction mechanisms are of substrate activation and the effects that determine the stereo- and regioselectivity of the reaction, the production of by-products in the reaction mechanism and the nature of the substrate and enzyme active site. The main focus of the chapter is the concept of the two-state reactivity and multistate reactivity of the high-valent iron(iv)-oxo reagent and how it affects the reactions mechanisms with substrates. Owing to the lack of experimental data on the active species of CYP 450 enzymes, computational studies have guided experiment. The emphasis of this chapter is mainly on the importance of theoretical and computational modeling on drug metabolism that is of enormous value to pharmaceutical applications of human cytochrome P450 enzymes.