Reconstitution of CYP3A4 active site through assembly of ligand interactions as a grid-template: Solving the modes of the metabolism and inhibition.

A hexagonal-grid based template system has been developed to a predicting tool of CYP3A4-mediated reactions through the reconstitution of the active site with the assembly of the ligands. Simultaneous interactions of flattened-shape ligands at two sites of CYP3A4, oxidizing- and triggering-sites, are essential ideas, which were supported in the simulation results of various ligands on the template. The interactions were accomplished with either uni-molecule bindings or bi-molecule bindings with ligands termed pro-metabolized and trigger molecules. The template shape was determined mainly through reciprocal comparisons of simulation results with available experiment data mainly on recombinant CYP3A4-mediated reactions of polyaromatic hydrocarbon (PAH) ligands. Through the applications of various PAH and non-PAH ligands on the template, couple region-specific interactions including mechanisms to facilitate ligand movement from the initial site to a place near heme-oxygen and to trigger of catalyses are envisioned. These are very effective tools to verify candidates of CYP3A4 ligands as the good or poor substrates. The bi-molecule binding idea also explains so called "cooperative bindings with activator/effector" as interactions with non-identical trigger molecules on this CYP3A4-template system, and also offers possible mechanisms of the non-linear kinetic behavior.