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Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study

Tandarić, Tana; Prah, Alja; Stare, Jernej; Mavri, Janez; Vianello, Robert (2020) Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond Study. International journal of molecular sciences, 21 (17). ISSN 1422-0067

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Abstract

Monoamine oxidases (MAOs) catalyze the degradation of a very broad range of biogenic and dietary amines including many neurotransmitters in the brain, whose imbalance is extensively linked with the biochemical pathology of various neurological disorders, and are, accordingly, used as primary pharmacological targets to treat these debilitating cognitive diseases. Still, despite this practical significance, the precise molecular mechanism underlying the irreversible MAO inhibition with clinically used propargylamine inhibitors rasagiline and selegiline is still not unambiguously determined, which hinders the rational design of improved inhibitors devoid of side effects current drugs are experiencing. To address this challenge, we present empirical valence bond QM/MM simulations of the rate-limiting step of the MAO inhibition involving the hydride anion transfer from the inhibitor α-carbon onto the N5 atom of the flavin adenin dinucleotide (FAD) cofactor. The proposed mechanism is strongly supported by the obtained free energy profiles, which confirm a higher reactivity of selegiline over rasagiline, while the calculated difference in the activation Gibbs energies of ∆∆G‡ = 3.1 kcal mol−1 is found to be in very good agreement with that from the measured literature kinact values that predict a 1.7 kcal mol−1 higher selegiline reactivity. Given the similarity with the hydride transfer mechanism during the MAO catalytic activity, these results verify that both rasagiline and selegiline are mechanism- based irreversible inhibitors and offer guidelines in designing new and improved inhibitors, which are all clinically employed in treating a variety of neuropsychiatric and neurodegenerative conditions.

Item Type: Article
Uncontrolled Keywords: irreversible inhibition ; monoamine oxidase ; hydride transfer ; antiparkinsonian drugs ; neurodegeneration ; flavoenzymes
Subjects: BIOMEDICINE AND HEALTHCARE > Pharmacy
Divisions: Division of Organic Chemistry and Biochemistry
Projects:
Project titleProject leaderProject codeProject type
Dizajn i sinteza novih dušikovih heterocikličkih fluorofora i fluorescentnih nanomaterijala kao kemijskih senzora za pH i metalne ione-iNFiNiTE–SENSRobert VianelloIP-2014-09-3386HRZZ
Depositing User: Robert Vianello
Date Deposited: 26 Nov 2020 09:07
Last Modified: 26 Nov 2020 09:07
URI: http://fulir.irb.hr/id/eprint/6016
DOI: 10.3390/ijms21176151

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