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

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 their usage abundance. The present system would offer practical way for structural identification and verification of CYP3A4-mediated metabolisms of various types of steroids.