Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

Fierro, Angélica; Edmondson, Dale E.; Celis-Barros, Cristián; Rebolledo-Fuentes, Marco; Zapata‐Torres, Gerald

doi:10.1371/journal.pone.0154989

Cited by 8 publications

(6 citation statements)

References 43 publications

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“…[141] The applications among the other studies are mainly in the validation domain for conserved water molecules in crystal structures. [142][143][144] WaterDock has been incorporated into another solvation program, Dowser++, to accurately predict water at protein interiors. [145] The latter is a development of the Dowser software, [146] performing the calculation on the whole protein space followed by further analysis.…”

Section: In Silico Methods Predicting Water Positionsmentioning

confidence: 99%

Advances in the Treatment of Explicit Water Molecules in Docking and Binding Free Energy Calculations

Maffucci

Contini

2020

CMC

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Section: In Silico Methods Predicting Water Positionsmentioning

confidence: 99%

Advances in the Treatment of Explicit Water Molecules in Docking and Binding Free Energy Calculations

Maffucci

Contini

2020

CMC

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“…Fierro et al have reported variation in the biological activity displayed by a couple of p ‐methoxy‐β‐methylphenethylamine ( p ‐MMP), where the inhibitor p ‐chloro‐β‐methylphenethylamine ( p ‐CMP) becomes a substrate when a methoxy group replaces its p ‐chloro substituent. Despite their structural and chemical commonalities, p ‐CMP and p ‐MMP displayed distinct inhibitory and substrate activities upon MAO‐B binding.…”

Section: Molecular Modeling Studies On Mao‐b and Its Inhibitorsmentioning

confidence: 99%

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Tripathi

Ayyannan

2019

Medicinal Research Reviews

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Monoamine oxidase (MAO) inhibitors have made significant contributions and remain an indispensable approach of molecular and mechanistic diversity for the discovery of antineurodegenerative drugs. However, their usage has been hampered by nonselective and/or irreversible action which resulted in drawbacks like liver toxicity, cheese effect, and so forth. Hence, the search for selective MAO inhibitors (MAOIs) has become a substantial focus in current drug discovery. This review summarizes our current understanding on MAO‐A/MAO‐B including their structure, catalytic mechanism, and biological functions with emphases on the role of MAO‐B as a potential therapeutic target for the development of medications treating neurodegenerative disorders. It also highlights the recent developments in the discovery of potential MAO‐B inhibitors (MAO‐BIs) belonging to diverse chemical scaffolds, arising from intensive chemical‐mechanistic and computational studies documented during past 3 years (2015‐2018), with emphases on their potency and selectivity. Importantly, readers will gain knowledge of various newly established MAO‐BI scaffolds and their development potentials. The comprehensive information provided herein will hopefully accelerate ideas for designing novel selective MAO‐BIs with superior activity profiles and critical discussions will inflict more caution in the decision‐making process in the MAOIs discovery.

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“…In addition to MAO enzymes, an EVB study supported by DFT cluster calculations suggests that the hydride transfer mechanism is involved in the function of the DAO enzyme [44]. Apart from EVB methodology, reactions catalyzed by MAO enzymes have been studied by the "traditional" QM/MM approach including DFT methodology in the quantum part [45], or by cluster models treated by DFT [37,46,47]. Furthermore, through a variety of simulation methods, we addressed the mechanism of irreversible inhibition of MAO-B by selegiline and rasagiline, together with their binding into the enzyme's active site [48], but also focusing on the rate-limiting step by the EVB approach [49].…”

Section: Introductionmentioning

confidence: 99%

Why Monoamine Oxidase B Preferably Metabolizes N-Methylhistamine over Histamine: Evidence from the Multiscale Simulation of the Rate-Limiting Step

Maršavelski

Mavri

Vianello

et al. 2022

IJMS

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Histamine levels in the human brain are controlled by rather peculiar metabolic pathways. In the first step, histamine is enzymatically methylated at its imidazole Nτ atom, and the produced N-methylhistamine undergoes an oxidative deamination catalyzed by monoamine oxidase B (MAO-B), as is common with other monoaminergic neurotransmitters and neuromodulators of the central nervous system. The fact that histamine requires such a conversion prior to oxidative deamination is intriguing since MAO-B is known to be relatively promiscuous towards monoaminergic substrates; its in-vitro oxidation of N-methylhistamine is about 10 times faster than that for histamine, yet this rather subtle difference appears to be governing the decomposition pathway. This work clarifies the MAO-B selectivity toward histamine and N-methylhistamine by multiscale simulations of the rate-limiting hydride abstraction step for both compounds in the gas phase, in aqueous solution, and in the enzyme, using the established empirical valence bond methodology, assisted by gas-phase density functional theory (DFT) calculations. The computed barriers are in very good agreement with experimental kinetic data, especially for relative trends among systems, thereby reproducing the observed MAO-B selectivity. Simulations clearly demonstrate that solvation effects govern the reactivity, both in aqueous solution as well as in the enzyme although with an opposing effect on the free energy barrier. In the aqueous solution, the transition-state structure involving histamine is better solvated than its methylated analog, leading to a lower barrier for histamine oxidation. In the enzyme, the higher hydrophobicity of N-methylhistamine results in a decreased number of water molecules at the active side, leading to decreased dielectric shielding of the preorganized catalytic electrostatic environment provided by the enzyme. This renders the catalytic environment more efficient for N-methylhistamine, giving rise to a lower barrier relative to histamine. In addition, the transition state involving N-methylhistamine appears to be stabilized by the surrounding nonpolar residues to a larger extent than with unsubstituted histamine, contributing to a lower barrier with the former.

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Why p-OMe- and p-Cl-β-Methylphenethylamines Display Distinct Activities upon MAO-B Binding

Cited by 8 publications

References 43 publications

Advances in the Treatment of Explicit Water Molecules in Docking and Binding Free Energy Calculations

Advances in the Treatment of Explicit Water Molecules in Docking and Binding Free Energy Calculations

Monoamine oxidase‐B inhibitors as potential neurotherapeutic agents: An overview and update

Why Monoamine Oxidase B Preferably Metabolizes N-Methylhistamine over Histamine: Evidence from the Multiscale Simulation of the Rate-Limiting Step

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