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

Research output: Contribution to journalArticle

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

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Cytochrome P-450 CYP3A
cytochromes
metabolism
Cytochromes
Metabolism
Discrete Fourier transforms
ketones
Conformations
alcohols
molecular dynamics
Ketones
Proteins
Oxidation
oxidation
Molecular dynamics
metabolites
Alcohols
axioms
hydrides
enzymes

All Science Journal Classification (ASJC) codes

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

Cite this

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

In: Journal of Molecular Modeling, Vol. 13, No. 6-7, 01.07.2007, p. 851-860.

Research output: Contribution to journalArticle

Shaikh, Abdul Rajjak ; Broclawik, Ewa ; Tsuboi, Hideyuki ; Koyama, Michihisa ; Endou, Akira ; Takaba, Hiromitsu ; Kubo, Momoji ; Carpio, Carlos A. ; Miyamoto, Akira. / 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. In: Journal of Molecular Modeling. 2007 ; Vol. 13, No. 6-7. pp. 851-860.
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