Predicting Regioselectivityand Lability of Cytochrome P450 Metabolism using Quantum Mechanical Simulations

Many computational methods have been developed that predict the regioselectivity of metabolism by drug metabolising isoforms of the Cytochrome P450 class of enzymes (P450) [1-5]. Here we describe recent developments to a method for predicting P450 metabolism that combines quantum mechanical (QM) simulations to estimate the reactivity of potential sites of metabolism on a compound with a ligand-based approach to account for the effects of orientation and steric constraints due to the binding pockets of different P450 isoforms. These new developments include modeling reaction pathways for epoxidations and developing new models for different P450 isoforms.

While valuable, predicting the relative proportion of metabolite formation at different sites on a compound is only a partial solution to designing more stable compounds. The advantage of a quantum mechanical approach is that it provides a quantitative estimate of the reactivity of each site, from which additional information can be derived regarding the vulnerability of each site to metabolism in absolute terms. One such measurement is the site lability, as calculated by StarDrop™ [6], which is a measure of the efficiency of the product formation step. This is an important factor influencing the rate of metabolism and we will illustrate how this provides valuable guidance regarding the potential to redesign compounds to overcome issues due to rapid P450 metabolism.