Oxidation mechanism in the metabolism of (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide on oxyferryl active site in CYP3A4 Cytochrome: DFT modeling.

The metabolism mechanism of (S)-N-[1-(3-morpholin-4ylphenyl)ethyl]-3-phenylacrylamide, mediated by CYP3A4 Cytochrome has been investigated by density functional QM calculations aided with molecular mechanics/molecular dynamics simulations. Two different orientations of phenyl ring for substrate approach toward oxyferryl center, imposing two subsequent rearrangement pathways have been investigated. Starting from sigma-complex in perpendicular orientation enzymatic mechanism involves consecutive proton shuttle intermediate, which further leads to the formation of alcohol and ketone. Parallel conformation leads solely to ketone product by 1,2 hydride shift. Although parallel and perpendicular sigma-complexes are energetically equivalent both for the gas phase or PCM solvent model, molecular dynamics studies in full CYP3A4 environment show that perpendicular conformation of the sigma-complex should be privileged, stabilized by hydrophobic interactions of phenylacrylamide chain. After assessing probability of the two conformations we postulate that the alcohol, accessible with the lowest energy barriers should be the major metabolite for studied substrate and CYP3A4 enzyme.