title: 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.
abstract: 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.
authors: Department of Applied Chemistry, Graduate School of Engineering, Tohoku University, 6-6-07 Aoba, Aramaki, Aoba-ku, Sendai, 980-8579, Japan.
authors: Abdul Rajjak
authors: AR
authors: Shaikh
authors: Ewa
authors: E
authors: Broclawik
authors: Hideyuki
authors: H
authors: Tsuboi
authors: Michihisa
authors: M
authors: Koyama
authors: Akira
authors: A
authors: Endou
authors: Hiromitsu
authors: H
authors: Takaba
authors: Momoji
authors: M
authors: Kubo
authors: Carlos A
authors: CA
authors: Del Carpio
authors: Akira
authors: A
authors: Miyamoto
mesh_terms: D000438:Alcohols / Q000138:chemical synthesis; D000465:Algorithms; D001665:Binding Sites; D002934:Cinnamates / Q000737:chemistry / Q000378:metabolism*; D003198:Computer Simulation; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry* / Q000378:metabolism; D006859:Hydrogen / Q000737:chemistry; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D007659:Ketones / Q000138:chemical synthesis; D053858:Metabolic Networks and Pathways; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D009025:Morpholines / Q000737:chemistry / Q000378:metabolism*; D009584:Nitrogen / Q000737:chemistry; D010084:Oxidation-Reduction; D010100:Oxygen / Q000737:chemistry; D011522:Protons; D011789:Quantum Theory; D015203:Reproducibility of Results; D055672:Static Electricity; D013379:Substrate Specificity
chemical_list: D000438:Alcohols; D002934:Cinnamates; D007659:Ketones; D009025:Morpholines; D011522:Protons; D006859:Hydrogen; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009584:Nitrogen; D010100:Oxygen