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

Theoretical investigation of the interactions in binding pocket of Reverse Transcriptase

AbstractInteractions in proteins have been studied using several chemical information techniques including quantum chemical methods that are applied to truncated systems composed of the ligand molecule and the surrounding amino acids of the receptor. In this work we adopt an approach to study these interactions accounting for as many as possible explicit solvent molecules and without the need of a fragmented calculation. Furthermore, we embed our quantum chemical calculations within a molecular dynamics framework that enables a fundamentally fast system for quantum molecular dynamic simulations (QCMD). Central to this new system for QCMD is the tight binding QC system, newly developed in our laboratories, and which combined with the MD paradigm results in an ultra accelerated QCMD method for protein–ligand interaction evaluations. We have applied our newly developed method to the Nevirapine (NVP)–Reverse Transcriptase (RT) system. We show how the proposed method leads us to new findings. The advanced QCMD was applied to a system of RT with NVP and it has led to the knowledge of specific groups and atoms that interact with surrounding amino acids of RT and help in drug binding. The information derived from this calculation may be used in designing drugs for NVP resistant virus strains that have binding capability like NVP

Interaction grand potential between calcium–silicate–hydrate nanoparticles at the molecular level

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