Prediction of regioselectivity and preferred order of CYP1A1-mediated metabolism: Solving the interaction of human and rat CYP1A1 forms with ligands on the template system

A simulation system for ligand interaction of human CYP1A1 has been developed using "Template" composed of hexagonal grids, as a modification of CYP1A2 system established previously. Differing from CYP1A2 Template, Site of Oxidation of CYP1A1 was located one-grid (Ring) away horizontally from Trigger-Region (Ring B) on CYP1A1 Template. Simultaneous interaction at Site of Oxidation and Trigger-Region as uni- or bi-molecule binding was maintained with CYP1A1 as well as CYP1A2 for the functional contributions. Reciprocal comparison of simulation results with experimental data suggested the access of ligands to Site of Oxidation inside of CYP1A1, through three distinct routes, termed Sideway, Center-Area and Thick-Area. To facilitate the verification of feasible placement(s), typical modes of the regional interactions have been defined and developed for prognostic devices. Simulation experiments of human and rat CYP1A1 offered possible causative mechanisms of the species difference as their distinct interactions near Site of Oxidation. The present CYP1A1 Template system has been proven to afford regio- and stereo-chemically feasible placements, through the use of the prognostic devices, of total of 353 CYP1A1-mediated reactions of 223 of distinct ligands, including substrates, inhibitors and poor substrates of drugs, environmental chemicals and endobiotics.