Does metabolism of (S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3- phenylacrylamide occur at the morpholine ring? Quantum mechanical and molecular dynamics studies

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

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

The mechanism of Cytochrome P450 3A4 mediated metabolism of (S)-N-[1-(3-morpholin-4ylphenyl)ethyl]-3-phenylacrylamide and its difluoro analogue have been investigated by density functional QM calculations aided with molecular mechanics/molecular dynamics simulations. In this article, we mainly focus on the metabolism of the morpholine ring of substrates 1 and 2. The reaction proceeds via a hydrogen atom abstraction from the morpholine ring by Compound I on a doublet potential energy surface. A transition state was observed at an O-H distance of 1.46 Å for 1 while 1.38 Å for 2. Transition state for the rebound mechanism was not observed. The energy barrier for the hydrogen atom abstraction from 1 was found to be 7.01 kcal/mol in gas phase while 19.53 kcal/mol when the protein environment was emulated by COSMO. Similarly the energy barrier for substrate 2 was found to be 11.07 kcal/mol in gas phase while it was reduced to 12.99 kcal/mol in protein environment. Our previous study reported energy barriers for phenyl hydroxylation of 7.4 kcal/mol. Large energy barriers for morpholine hydroxylation indicates that hydroxylation at the phenyl ring may be preferred over morpholine. MD simulations in protein environment indicated that hydrogen atom at C4 position of phenyl ring remains in closer proximity to oxyferryl oxygen of the heme moiety as compared to morpholine hydrogen and hence greater chance to metabolize at phenyl ring.

Original languageEnglish
Pages (from-to)740-744
Number of pages5
JournalMaterials Transactions
Volume48
Issue number4
DOIs
Publication statusPublished - Apr 1 2007

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Energy barriers
metabolism
Metabolism
Hydroxylation
Molecular dynamics
molecular dynamics
Hydrogen
rings
hydrogen atoms
Proteins
Atoms
proteins
Potential energy surfaces
Gases
Molecular mechanics
vapor phases
Substrates
Cytochrome P-450 CYP3A
energy
cytochromes

All Science Journal Classification (ASJC) codes

  • Materials Science(all)
  • Metals and Alloys

Cite this

Does metabolism of (S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3- phenylacrylamide occur at the morpholine ring? Quantum mechanical and molecular dynamics studies. / Shaikh, Abdul Rajjak; Del Carpio, Carlos A.; Tsuboi, Hideyuki; Koyama, Michihisa; Hatakeyama, Nozomu; Endou, Akira; Takaba, Hiromitsu; Kubo, Momoji; Broclawik, Ewa; Miyamoto, Akira.

In: Materials Transactions, Vol. 48, No. 4, 01.04.2007, p. 740-744.

Research output: Contribution to journalArticle

Shaikh, AR, Del Carpio, CA, Tsuboi, H, Koyama, M, Hatakeyama, N, Endou, A, Takaba, H, Kubo, M, Broclawik, E & Miyamoto, A 2007, 'Does metabolism of (S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3- phenylacrylamide occur at the morpholine ring? Quantum mechanical and molecular dynamics studies', Materials Transactions, vol. 48, no. 4, pp. 740-744. https://doi.org/10.2320/matertrans.48.740
Shaikh, Abdul Rajjak ; Del Carpio, Carlos A. ; Tsuboi, Hideyuki ; Koyama, Michihisa ; Hatakeyama, Nozomu ; Endou, Akira ; Takaba, Hiromitsu ; Kubo, Momoji ; Broclawik, Ewa ; Miyamoto, Akira. / Does metabolism of (S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3- phenylacrylamide occur at the morpholine ring? Quantum mechanical and molecular dynamics studies. In: Materials Transactions. 2007 ; Vol. 48, No. 4. pp. 740-744.
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