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

Abdul Rajjak Shaikh, Ewa Broclawik, Hideyuki Tsuboi, Michihisa Koyama, Akira Endou, Hiromitsu Takaba, Momoji Kubo, Carlos A. Carpio, Akira Miyamoto

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    4 Citations (Scopus)

    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 σ-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 σ-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 σ-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.

    Original languageEnglish
    Pages (from-to)851-860
    Number of pages10
    JournalJournal of Molecular Modeling
    Volume13
    Issue number6-7
    DOIs
    Publication statusPublished - Jul 1 2007

    All Science Journal Classification (ASJC) codes

    • Catalysis
    • Computer Science Applications
    • Physical and Theoretical Chemistry
    • Organic Chemistry
    • Computational Theory and Mathematics
    • Inorganic Chemistry

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