Quantum chemical modeling of the inhibition mechanism of monoamine oxidase by oxazolidinone and analogous heterocyclic compounds

The flavoenzyme monoamine oxidase (MAO) is essential for the enzymatic decomposition of neurotransmitters. While it is commonly accepted that the rate limiting step of the reaction is the stereoselective abstraction of a hydrogen from the substrate, the precise mechanism is unknown. We modeled the reaction of human MAO-B with benzylamine by means of QM/MM calculations based on density functional theory. Oxidation of the unprotonated substrate was found to proceed with rates in good agreement with experimental values, while the protonated substrate does not react at room temperature. Our results support a concerted asynchronous polar nucleophilic mechanism. The lone pair of the amine-nitrogen interacts with a carbon atom of the flavin cofactor. During the reaction, this lone pair, as well as a proton, are transferred to the cofactor. Analysis of the electronic structure during the reaction rules out a radical mechanism.

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“…MAO inhibitors also have been studied both experimentally , and theoretically − because of their potential use as pharmaceutical products.…”

Section: Introductionmentioning

confidence: 99%

Reaction Mechanism of Monoamine Oxidase from QM/MM Calculations

2013

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“…(3 R ,5 S )-5-(Aminomethyl)-3-(4-methoxyphenyl)dihydrofuran-2(3 H )-one ((3 R ,5 S )- 168 ) was discovered as a potential medication in Parkinson’s disease [99]. Synthesis of enantiomerically pure (3 R ,5 S )- 168 could be accomplished from the aziridine aldehyde (2 S ,1' R )- 6 because the butyrolactone ring formation would proceed with inversion of configuration at C2 in the aziridine ring (Scheme 43) [100].…”

Section: Reviewmentioning

confidence: 99%

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

Głowacka¹,

Trocha²,

Wróblewski³

et al. 2019

Beilstein J. Org. Chem.

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Since Garner’s aldehyde has several drawbacks, first of all is prone to racemization, alternative three-carbon chirons would be of great value in enantioselective syntheses of natural compounds and/or drugs. This review article summarizes applications of N-(1-phenylethyl)aziridine-2-carboxylates, -carbaldehydes and -methanols in syntheses of approved drugs and potential medications as well as of natural products mostly alkaloids but also sphingoids and ceramides and their 1- and 3-deoxy analogues and several hydroxy amino acids and their precursors. Designed strategies provided new procedures to several drugs and alternative approaches to natural products and proved efficiency of a 2-substituted N-(1-phenylethyl)aziridine framework as chiron bearing a chiral auxiliary.

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“…4 for the 5-(aminomethyl)-3-(4-methoxyphenyl)-2-oxazolidinone which is a well-known time-dependent inactivator of MAO-B. 6,53,54 The PC inv and N5 yl analogs of 5-(aminomethyl)-3-(4-methoxyphenyl)-2-oxazolidinone were optimized (Fig. S1 †) with the same methodology (M06-2X/6-31+G(d,p):PM6) as for serotonin.…”

Section: Mechanism-based Rational Design Of Covalent Reversible Inhib...mentioning

confidence: 99%

ONIOM calculations on serotonin degradation by monoamine oxidase B: insight into the oxidation mechanism and covalent reversible inhibition

2016

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Monoamine oxidase (MAO) is an enzyme which catalyzes the oxidation of neurotransmitter amines and regulates their level. There are two forms of the enzyme with 70% similarity, known as MAO-A and MAO-B. MAO inhibitors are used in the treatment of neurological disorders such as depression, Parkinson's and Alzheimer's diseases. Therefore, understanding the chemical steps of MAO catalyzed amine oxidation is crucial for rational drug design. However, despite many experimental studies and recent computational efforts in the literature, the amine oxidation mechanism by MAO enzymes is still controversial. The polar nucleophilic mechanism and hydride transfer mechanisms are under debate in recent QM/MM studies. In this study, the serotonin oxidation mechanism by MAO was explored via the ONIOM (QM : QM) methodology at the M06-2X/6-31+G(d,p):PM6 level. A modified MAO mechanism involving a covalent reversible inhibition step via formation of flavin N5 ylide was proposed. This mechanism can be used to modulate the potency and reversibility of novel mechanism-based covalent inhibitors by intelligent modifications of the structure of the inhibitors. NBO donor-acceptor analysis confirms that the rate-determining αC-H cleavage step is a hybrid of hydride and proton transfer where hydride transfer dominates over the proton transfer. The functional role of covalent FAD was also investigated by calculating the activation energy of noncovalent FAD models where a 22 fold decrease in the rate of catalysis was predicted. Geometrical features imply that the function of the covalent bond in FAD might be to maintain the correct geometry and conformation for a more efficient catalysis.

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Quantum chemical modeling of the inhibition mechanism of monoamine oxidase by oxazolidinone and analogous heterocyclic compounds

Cited by 9 publications

References 42 publications

Reaction Mechanism of Monoamine Oxidase from QM/MM Calculations

Reaction Mechanism of Monoamine Oxidase from QM/MM Calculations

N-(1-Phenylethyl)aziridine-2-carboxylate esters in the synthesis of biologically relevant compounds

ONIOM calculations on serotonin degradation by monoamine oxidase B: insight into the oxidation mechanism and covalent reversible inhibition

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