Recognition of trans and gauche phenylethylamine conformers in the active site of human monoamine oxidase B: A MD-simulation and DFT studies

Abstract Phenylethylamine (PEA) is an endogenous amphetamine and as such, it blocks monoamine transporters and to a lesser extent vesicular transport thus elevating the level of corresponding neurotransmitter molecules at the synaptic cleft. In the physiological system, PEA acts as neuromodulator and is primarily metabolized by human monoamine oxidase B (hMAO B) to corresponding aldehyde and ammonia. In this work the stabilization of trans and gauche conformers of protonated phenylethylamine in the active site cavity of hMAO B have been evaluated by MD-simulation and DFT studies. The aromatic phenyl ring of trans -PEA is stabilized by Phe343(π)⋯PEA(π) interaction, where the π-ring of Phe343 is observed to stabilized by π⋯H O (Tyr398 OH ) interaction, whereas in gauche conformer hydrogen bonding association of a water molecule with N + -atom of PEA and at the same time its bridging with aromatic π-ring of that substrate through non-covalent (N + ⋯W⋯π and water⋯π⋯water) interaction have provided some extra stability to it. It has also been observed that N + -site of PEA has been stabilized by two to three water molecules along with Leu171 OB and Gln206 OE1 /Tyr435 OH in the respective trans and gauche conformers. The results provide some interesting chemical insight on the stabilization of both the trans and gauche conformers of PEA in the active site of hMAO B which may be useful for inhibitor design related to neurological diseases.