Solving the interactions of steroidal ligands with CYP3A4 using a grid-base template system.

Solving the interactions of steroidal ligands with CYP3A4 using a grid-base template system. Drug Metab Pharmacokinet. 2019 May 31;: Authors: Goto T, Tohkin M, Yamazoe Y Abstract Using over fifty steroidal ligands, CYP3A4 Template system established in our previous study (DMPK 34: 113-125, 2019) has been evaluated for the applicability for prediction of regioselective metabolisms of steroids in the present study. Plural regional interactions near Site of Oxidation of CYP3A4 (Slide-down and Adaptation) are newly defined for steroid ligands in addition to previously characterized Trigger- and IJL-interactions on Template. Interaction of steroids at ring-A with CYP3A4 residue (Front-residue), at the facial side of Ring B of Template, determined the availability of ligand sitting at Rings A and B of Template. Steroids having 3-one-4-ene structures, which are not stacked on Front-residue, thus slide down for their 6-oxidations. Some steroids with 3β-ol structures undergo the further right-side movement (Adaptation) for their 7-oxidations. Similar overpassing phenomena are also expected for steroid 15/16-oxidations and 2/1-oxidations. Allowable width on ligand accommodation was also defined as Width-gauge of Template. Reciprocal comparison of sittings of steroids on Template with experimental data offered idea of CYP3A4-mediated oxidations of steroids through seven distinct types of placements on Template and of the relationship with thei...
Source: Drug Metabolism and Pharmacokinetics - Category: Drugs & Pharmacology Tags: Drug Metab Pharmacokinet Source Type: research