Quantum chemical study on the oxidation process of a hydrogen terminated Si surface

科研費報告書収録論文(課題番号:09450296・基盤研究(B)(2)・H9～H10/研究代表者:宮本, 明/新しい高速化第一原理分子動力学計算プログラムの開発と金属超微粒子触媒への応用

Does Metabolism of (S)-N-[1-(3-Morpholin-4-ylphenyl)ethyl]-3-phenylacrylamide Occur at the Morpholine Ring? Quantum Mechanical and Molecular Dynamics Studies

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