Significance Statement In this study, we reported for the first time the covalent MBI of CYP3A by PEM and deciphered its bioactivation pathway involving the metabolic activation of PEM and its major O-desmethylated metabolite to reactive iminium ion intermediates. Following which, a unique covalent docking methodology was harnessed to unravel the structural and molecular determinants underpinning its inactivation. Findings from our study lay the foundation for future investigation of clinically-relevant drug-drug interactions between PEM and concomitant substrates of CYP3A.
ReadIn this study, we reported for the first time the covalent MBI of CYP3A by PEM and deciphered its bioactivation pathway involving the metabolic activation of PEM and its major O-desmethylated metabolite to reactive iminium ion intermediates. Following which, a unique covalent docking methodology was harnessed to unravel the structural and molecular determinants underpinning its inactivation. Findings from our study lay the foundation for future investigation of clinically-relevant drug-drug interactions between PEM and concomitant substrates of CYP3A.
Read