Deciphering Key Interactions of Ligands with CYP3A4-Template* system

Abstract

Cytochrome P450 (CYP)-mediated metabolisms are often associated with biological and toxicological events of chemicals. A major hepatic enzyme, CYP3A4, showed clear distinctions on their catalyses even among ligands having resemble structures. To better understand mechanisms of their distinct catalyses, possible associations of ligand interactions at specific parts of CYP3A4 residues were investigated using CYP3A4-Template system developed (DMPK 2019 and 2020). A placement was available selectively for CYP3A4-mediated R-thalidomide 5-oxidation on Template, but not for the 5'-oxidation and the S-isomer oxidations. Similar placements were generated for pomalidomide (4-amino-thalidomide), but not for a poor ligand, lenalidomide (3-deoxy-pomalidomide). The latter ligand took placements lacking IJK-Interaction or sticking the 4-amino part beyond the facial-side wall on Template. A placement was available for the tert-butyl oxidation of terfenadine, but not for an analog, ebastine. Their interactions with upper-Cavity-2 residue were expected to differ at their sites of oxygen substituents. Some phenolic antioxidants behave distinctly toward biological oxidations in vitro and in vivo. Butylated hydroxytoluene is oxidized to the peroxy-derivative in vitro, but solely to the oxidized metabolites at the benzyl and tert-butyl methyl positions in vivo. Involvement of CYP3A4 were suggested for all the three reactions from the placements on Template. Tocopherols were also applied on Template for the oxidations for chroman and side-chain terminals. The primary placement was suggested to undergo the futile-recycling through formation of the peroxide intermediate subsequently to lead the substantial lack of the CYP3A4-mediated oxidation. These data suggest the effectiveness of CYP3A4-Template assessment to understand the causal basis of poor oxidations and also to verify the in vivo contribution of CYP3A4-mediated peroxidative reactions.

Application of CYP1A2-Template System to Understand Metabolic Processes in the Safety Assessment

“…1 D, 2 G and 3 D). The results obtained in the present and previous studies 1 , 2 , 8 , 9 ) suggest our CYP Template systems as effective tools to warn an appearance of unstable reactive intermediates. Our CYP-Template systems would support confident judgements in safety assessments through offering the mechanistic understandings of the metabolism.…”

“…Placements of ligands on Template systems of human CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3As offered the information on sites of metabolisms regio- and stereo-selectively with more than 99% of accuracies. These Template systems are shown as effective tools for drug metabolism prediction and safety assessment 8 , 9 , 10 ) .…”

Application of fused-grid-based CYP-Template systems for genotoxic substances to understand the metabolisms

“…Cavity-2 (Trigger) residue stays initially around Position 53 and near Rear-wall, and then slides down to Position 26 after the arrival of ligands at Site of oxidation. Presence at the initial Position of Cavity-2 residue sometimes interferes the ligand migrations like the cases of clarithromycin [ 12 ] and ebastine [ 15 ], and restricts the migration of ligands beyond trigger-site (Position 26). Ligands are thus able to pass a space around Facial-wall, but not a space center to Rear-wall, around Cavity-2 residue.…”

“…Ligands are thus able to pass a space around Facial-wall, but not a space center to Rear-wall, around Cavity-2 residue. Detailed procedures are described in our publications [ 12 – 15 , 22 , 23 ].…”