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 language | English |
|---|---|
| Pages (from-to) | 851-860 |
| Number of pages | 10 |
| Journal | Journal of Molecular Modeling |
| Volume | 13 |
| Issue number | 6-7 |
| DOIs | |
| Publication status | Published - Jul 1 2007 |
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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 journal › Article
}
TY - JOUR
T1 - Oxidation mechanism in the metabolism of (S)-N-[1-(3-morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide on oxyferryl active site in CYP3A4 Cytochrome
T2 - DFT modeling
AU - Shaikh, Abdul Rajjak
AU - Broclawik, Ewa
AU - Tsuboi, Hideyuki
AU - Koyama, Michihisa
AU - Endou, Akira
AU - Takaba, Hiromitsu
AU - Kubo, Momoji
AU - Carpio, Carlos A.
AU - Miyamoto, Akira
PY - 2007/7/1
Y1 - 2007/7/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=34347376517&partnerID=8YFLogxK
U2 - 10.1007/s00894-007-0196-5
DO - 10.1007/s00894-007-0196-5
M3 - Article
C2 - 17387527
AN - SCOPUS:34347376517
VL - 13
SP - 851
EP - 860
JO - Journal of Molecular Modeling
JF - Journal of Molecular Modeling
SN - 1610-2940
IS - 6-7
ER -