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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

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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.

Orientation of phenyl ring towards porphyrin plane selected by substrate interaction with enzymatic cavity channels enzymatic reaction

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Acknowledgements

We thank Prof. G. D. Szklarz and Mr. Spencer Ericksen, Department of Basic Pharmaceutical Sciences, West Virginia University for kindly providing us CVFF parameters for heme moiety.

This study was partly sponsored by the Polish State Committee for Scientific Research (Grant No. 2 P04A 042 26).

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Authors and Affiliations

  1. Department of Applied Chemistry, Graduate School of Engineering, Tohoku University, 6-6-07 Aoba, Aramaki, Aoba-ku, Sendai, 980-8579, Japan

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

  2. Institute of Catalysis, Polish Academy of Sciences, ul. Niezapominajek 8, Kraków, 30-239, Poland

    Ewa Broclawik

  3. PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama, 332-0012, Japan

    Momoji Kubo

  4. New Industry Creation Hatchery Centre, Tohoku University, 6-6-10 Aoba, Aramaki, Aoba-ku, Sendai, 980-8579, Japan

    Akira Miyamoto

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  1. Abdul Rajjak Shaikh
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  2. Ewa Broclawik
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Correspondence to Ewa Broclawik.

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Shaikh, A.R., Broclawik, E., Tsuboi, H. et al. 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. J Mol Model 13, 851–860 (2007). https://doi.org/10.1007/s00894-007-0196-5

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  • DOI: https://doi.org/10.1007/s00894-007-0196-5

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