Development of template systems for ligand interactions of CYP3A5 and CYP3A7 and their distinctions from CYP3A4 template

Abstract Starting from established CYP3A4 Template (DMPK. 2019, and 2020), CYP3A5 and CYP3A7 Templates have been constructed to be reliable tools for verification of their distinct catalytic properties. A distinct occupancy was observed on CYP3A4-selective ligands, but not on the non-selective ligands, in simulation experiments. These ligands often invade into Bay-1 region during the migration from Entrance to Site of oxidation in simulation experiments. These results offered an idea of the distinct localization of Bay-1 residue on CYP3A5 Template, in which the Bay-1 residue stayed closely to Template border. The idea also accounted for the higher oxidation rates of CYP3A5, than of CYP3A4, of noscapine and schisantherin E through their enhanced sitting-stabilization. Typical CYP3A7 substrates such as zonisamide and retinoic acids took their placements without occupying a left side region of Template for their metabolisms. In turn, the occupancies of the left-side region were inevitably observed among poor ligands of CYP3A7. Altered extent of IJK-Interaction or localization of a specific residue at the left-side would thus explain distinct catalytic properties of CYP3A7 on Template. These data suggest the alteration of each one of Template region, from CYP3A4 Template, led to the distinct catalytic properties of CYP3A5 and CYP3A7 forms.