Quantum chemical study of the hydrolysis of oxidized endogenous psychedelic N,N-dimethyltryptamine

The metabolism of biogenic N,N-dimethyltryptamine (DMT) starts with its enzymatic oxidation to indole-3-N,N-dimethylethaniminium cation (imDMT(+)) by monoamine oxidase (MAO). Following this reaction, a nonenzymatic hydrolysis occurs, yielding indole-3-acetaldehyde (IAL) and dimethylamine (DMA). In our in silico study, using a hybrid DFT method at the M06-2X/aug-cc-pVDZ level, we examined the necessity of explicit water molecules to accurately model the hydrolysis. Our calculations revealed that despite an implicit continuum solvent model, one or two explicit solvent molecules should be added to obtain meaningful activation barriers. Thus, we demonstrate that the hydrolysis can occur in a human cell without enzymatic assistance, paving the way for deeper understanding of DMT metabolism

The Use of Multiscale Molecular Simulations in Understanding a Relationship between the Structure and Function of Biological Systems of the Brain: The Application to Monoamine Oxidase Enzymes

Computational techniques provide accurate descriptions of the structure and dynamics of biological systems, contributing to their understanding at an atomic level.Classical MD simulations are a precious computational tool for the processes where no chemical reactions take place.QM calculations provide valuable information about the enzyme activity, being able to distinguish among several mechanistic pathways, provided a carefully selected cluster model of the enzyme is considered.Multiscale QM/MM simulation is the method of choice for the computational treatment of enzyme reactions offering quantitative agreement with experimentally determined reaction parameters.Molecular simulation provide insight into the mechanism of both the catalytic activity and inhibition of monoamine oxidases, thus aiding in the rational design of their inhibitors that are all employed and antidepressants and antiparkinsonian drugs. Aging society and therewith associated neurodegenerative and neuropsychiatric diseases, including depression, Alzheimer's disease, obsessive disorders, and Parkinson's disease, urgently require novel drug candidates. Targets include monoamine oxidases A and B (MAOs), acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and various receptors and transporters. For rational drug design it is particularly important to combine experimental synthetic, kinetic, toxicological, and pharmacological information with structural and computational work. This paper describes the application of various modern computational biochemistry methods in order to improve the understanding of a relationship between the structure and function of large biological systems including ion channels, transporters, receptors, and metabolic enzymes. The methods covered stem from classical molecular dynamics simulations to understand the physical basis and the time evolution of the structures, to combined QM, and QM/MM approaches to probe the chemical mechanisms of enzymatic activities and their inhibition. As an illustrative example, the later will focus on the monoamine oxidase family of enzymes, which catalyze the degradation of amine neurotransmitters in various parts of the brain, the imbalance of which is associated with the development and progression of a range of neurodegenerative disorders. Inhibitors that act mainly on MAO A are used in the treatment of depression, due to their ability to raise serotonin concentrations, while MAO B inhibitors decrease dopamine degradation and improve motor control in patients with Parkinson disease. Our results give strong support that both MAO isoforms, A and B, operate through the hydride transfer mechanism. Relevance of MAO catalyzed reactions and MAO inhibition in the context of neurodegeneration will be discussed

A comparative computational investigation on the proton and hydride transfer mechanisms of monoamine oxidase using model molecules

Monoamine oxidase (MAO) enzymes regulate the level of neurotransmitters by catalyzing the oxidation of various amine neurotransmitters, such as serotonin, dopamine and norepinephrine. Therefore, they are the important targets for drugs used in the treatment of depression, Parkinson, Alzeimer and other neurodegenerative disorders. Elucidation of MAO-catalyzed amine oxidation will provide new insights into the design of more effective drugs. Various amine oxidation mechanisms have been proposed for MAO so far, such as single electron transfer mechanism, polar nucleophilic mechanism and hydride mechanism. Since amine oxidation reaction of MAO takes place between cofactor flavin and the amine substrate, we focus on the small model structures mimicking flavin and amine substrates so that three model structures were employed. Reactants, transition states and products of the polar nucleophilic (proton transfer), the water-assisted proton transfer and the hydride transfer mechanisms were fully optimized employing various semi-empirical, ab initio and new generation density functional theory (DFT) methods. Activation energy barriers related to these mechanisms revealed that hydride transfer mechanism is more feasible. (C) 2013 Elsevier Ltd. All rights reserved