The kinetic mechanism for cytochrome P450 metabolism of type II binding compounds: evidence supporting direct reduction.

ABSTRACT: The metabolic stability of a drug is an important property that should be optimized during drug design and development. Nitrogen incorporation is hypothesized to increase the stability by coordination of nitrogen to the heme iron of cytochrome P450, a binding mode that is referred to as type II binding. However, we noticed that the type II binding compound 1 has less metabolic stability at sub-saturating conditions than a closely related type I binding compound 3. Three kinetic models will be presented for type II binder metabolism; (1) Dead-end type II binding, (2) a rapid equilibrium between type I and II binding modes before reduction, and (3) a direct reduction of the type II coordinated heme. Data will be presented on reduction rates of iron, the off rates of substrate (using surface

SUBMITTER: Pearson J 

PROVIDER: S-EPMC3115501 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature