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An insight into the mechanism of the irreversible inhibition of monoamine oxidase enzymes by propargylamine inhibitors

Monoamine oxidases (MAOs) are flavoenzymes that catalyze the degradation of a range of brain neurotransmitters, whose imbalance is extensively linked with the pathology of various neurological disorders. This is why MAOs have been the central pharmacological targets in treating neurodegeneration for more than 60 years. Still, despite this practical importance, the precise chemical mechanisms underlying the irreversible inhibition of the MAO B isoform with clinical drugs rasagiline (RAS) and selegiline (SEL) remained unknown. We employed a combination of MD simulations, MM-GBSA binding free energy evaluations, QM cluster calculations1 and EVB simulations2 to show that the MAO inactivation proceeds in three steps, where, in the rate- limiting first step, FAD utilizes its N5 atom to abstracts a hydride anion from the inhibitor α-CH2 group to ultimately give the final inhibitor-FAD adduct matching crystallographic data. The obtained free energy profiles reveal a lower activation energy for SEL by 3.1 kcal mol–1 , being in excellent agreement with experimental ΔΔG ‡ EXP = 1.7 kcal mol–1 , thus rationalizing its higher in vivo reactivity over RAS and supporting the validity of the proposed mechanism. The calculated ΔGBIND energies confirm SEL binds better due to its bigger size and flexibility allowing it to optimize the hydrophobic C–H•••π and π•••π interactions with residues throughout both of enzyme's cavities, particularly with FAD, Gln206 and four active site tyrosines, thus overcoming a larger ability of RAS to form hydrogen bonds that only position it in less reactive orientations for the hydride abstraction. Accordingly, desmethyl-SEL turned out to be the least effective inhibitor, while the N-methyl analogue of RAS is identified as the most potent compounds, and its further experimental characterization is strongly recommended. Offered results elucidate structural determinants affecting the affinity and rates of the inhibition reaction that should be considered to cooperate when designing more effective compounds devoid of untoward effects, which are of utmost significance and urgency with the growing prevalence of brain diseases.

mao enzymes, computational chemistry, enyzme inhibition, empirical valence bond, molecular dynamics

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