1 research outputs found
A Pragmatic Approach Using First-Principle Methods to Address Site of Metabolism with Implications for Reactive Metabolite Formation
A majority of xenobiotics are metabolized by cytochrome
P450 (CYP)
enzymes. The discovery of drug candidates with low propensity to form
reactive metabolites and low clearance can be facilitated by understanding
CYP-mediated xenobiotic metabolism. Being able to predict the sites
where reactive metabolites form is beneficial in drug design to produce
drug candidates free of reactive metabolite issues. Herein, we report
a pragmatic protocol using first-principle density functional theory
(DFT) calculations for predicting sites of epoxidation and hydroxylation
of aromatic substrates mediated by CYP. The method is based on the
relative stabilities of the CYP-substrate intermediates or the substrate
epoxides. Consequently, it concerns mainly the electronic reactivity
of the substrates. Comparing to the experimental findings, the presented
protocol gave excellent first-ranked epoxidation site predictions
of 83%, and when the test was extended to CYP-mediated sites of aromatic
hydroxylation, satisfactory results were also obtained (73%). This
indicates that our assumptions are valid and also implies that the
intrinsic reactivities of the substrates are in general more important
than their binding poses in proteins, although the protocol may benefit
from the addition of docking information