Prediction of Cytochrome P450 Xenobiotic Metabolism: Tethered Docking and Reactivity Derived from Ligand Molecular Orbital Analysis

Metabolism of xenobiotic and endogenous
compounds is frequently
complex, not completely elucidated, and therefore often ambiguous.
The prediction of sites of metabolism (SoM) can be particularly helpful
as a first step toward the identification of metabolites, a process
especially relevant to drug discovery. This paper describes a reactivity
approach for predicting SoM whereby reactivity is derived directly
from the ground state ligand molecular orbital analysis, calculated
using Density Functional Theory, using a novel implementation of the
average local ionization energy. Thus each potential SoM is sampled
in the context of the whole ligand, in contrast to other popular approaches
where activation energies are calculated for a predefined database
of molecular fragments and assigned to matching moieties in a query
ligand. In addition, one of the first descriptions of molecular dynamics
of cytochrome P450 (CYP) isoforms 3A4, 2D6, and 2C9 in their Compound
I state is reported, and, from the representative protein structures
obtained, an analysis and evaluation of various docking approaches
using GOLD is performed. In particular, a covalent docking approach
is described coupled with the modeling of important electrostatic
interactions between CYP and ligand using spherical constraints. Combining
the docking and reactivity results, obtained using standard functionality
from common docking and quantum chemical applications, enables a SoM
to be identified in the top 2 predictions for 75%, 80%, and 78% of
the data sets for 3A4, 2D6, and 2C9, respectively, results that are
accessible and competitive with other recently published prediction
tools.