CYP1B1- and CYP1A1-Template systems and their application to metabolism and inhibition

Prediction of cytochrome P450 (CYP)-mediated metabolism is crucial for assessing the safety of chemicals. An in silico system to reproduce CYP1B1-mediated reactions has been developed by the reverse construction of ligand-accessible spaces from ligand assemblies as a fused grid Template* system. There are close similarities between Templates of CYP1B1 and previously established CYP1A1 (Genes & Environ 2023) in the distribution area, Site of oxidation, and the available Width, except for the use of Position 52’ (Pier-sitting) and the lack of use of the bottom in the middle region (Rings F and Ea) on CYP1B1-Template. Experiments using various substrates of both enzymes further suggested the distinct localization of Bay-2 residues on Templates of CYP1A1 and CYP1B1. More than 260 reactions of CYP1A1/1B1 ligands were examined on the present CYP1A1- and CYP1B1-Template systems. From their placements on the Templates and rules for interaction modes, verifications of good and poor substrates, regio/stereo-selectivity, and inhibition became faithfully available for these ligands. To understand the structural basis of the inhibitory interaction, various inhibitors were applied to the Templates and verified modes of the steric interactions. Both the hangings at Position 32 of CYP1A1 ligands and the adherence at Positions 24–52 of CYP1B1 ligands are suggested to retard the dissociation of Bay-2 residues from ligand molecules. Dissociation interference of ligands with Bay-2 residue is thus possible to be a mechanism of ligand-mediated inhibition on CYP1A1 and CYP1B1.