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Versatile applicability of a grid-based CYP3A4 Template to understand the interacting mechanisms with the small-size ligands; part 3 of CYP3A4 Template study.

Y. Yamazoe,Takahiro Goto,M. Tohkin

Published 2020 in Drug Metabolism and Pharmacokinetics

ABSTRACT

Modes of interactions of small ligands with CYP3A4 have been defined using the Template established in our previous studies (DMPK. 34: 113-125 2019 and 34 351-364 2019). Interactions of polyaromatic hydrocarbons such as benzo[a]pyrene, pyrene and dibenzo[a,j]acridine were refined with the idea of Right-side movement of ligands at Rings A and B of Template. Expected formation of metabolites from the placements faithfully matched with experimentally observed sites of their metabolisms and also with preferred orders of regio-isomeric metabolite abundances in recombinant CYP3A4 system. In comparison of CYP3A4-ligand data with the placements on simulations, a futile sitting of non-substituted and free rotatable phenyl structures was suggested as a cause of poor oxidations of the phenyl parts of CYP3A4 ligands. These data were in turn indicative of the role of the rotation-ceasing action for the function. Typical inhibitors, ketoconazole, nicardipine, mibefradil and GF-I-1 shared mutuality on their sittings, in which the inhibitor molecules hold a CYP3A4 residue from dual sides on Template. In addition, clotrimazole would be stuck between facial- and rear-side walls of CYP3A4 and interact with ferric iron through nitrogen atom of the imidazole part. These data offered structural bases of CYP3A4-inhibitory actions of ligands.

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