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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.
- Source :
-
Drug metabolism and pharmacokinetics [Drug Metab Pharmacokinet] 2020 Jun; Vol. 35 (3), pp. 253-265. Date of Electronic Publication: 2020 Jan 24. - Publication Year :
- 2020
-
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.<br /> (Copyright © 2020 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.)
- Subjects :
- Coumarins pharmacology
Cytochrome P-450 CYP3A metabolism
Cytochrome P-450 CYP3A Inhibitors pharmacology
Humans
Ketoconazole pharmacology
Ligands
Mibefradil pharmacology
Molecular Structure
Nicardipine pharmacology
Coumarins chemistry
Cytochrome P-450 CYP3A chemistry
Cytochrome P-450 CYP3A Inhibitors chemistry
Ketoconazole chemistry
Mibefradil chemistry
Nicardipine chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1880-0920
- Volume :
- 35
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Drug metabolism and pharmacokinetics
- Publication Type :
- Academic Journal
- Accession number :
- 32331852
- Full Text :
- https://doi.org/10.1016/j.dmpk.2020.01.001