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Computational Insight into the Mechanism of the Irreversible Inhibition of Monoamine Oxidase Enzymes by the Antiparkinsonian Propargylamine Inhibitors Rasagiline and Selegiline

  • Tana Tandarić
    Tana Tandarić
    Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia
  •  and 
  • Robert Vianello*
    Robert Vianello
    Computational Organic Chemistry and Biochemistry Group, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia
    *Tel.: +385-1-4561117. Fax: +385-1-4680084. E-mail: [email protected]
Cite this: ACS Chem. Neurosci. 2019, 10, 8, 3532–3542
Publication Date (Web):June 17, 2019
Copyright © 2019 American Chemical Society

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    Abstract Image

    Monoamine oxidases (MAOs) are flavin adenine dinucleotide containing 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. Here we employed a combination of MD simulations, MM-GBSA binding free energy evaluations, and QM cluster calculations to show 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 1.2 kcal mol–1 and a higher reaction exergonicity by 0.8 kcal mol–1, with the former being in excellent agreement with experimental ΔΔGEXP = 1.7 kcal mol–1, thus rationalizing its higher in vivo reactivity over RAS. The calculated ΔGBIND energies confirm SEL binds better due to its bigger size and flexibility allowing it to optimize 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. 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.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acschemneuro.9b00147.

    • Full details of the simulation setup, Cartesian coordinates for computed stationary points, various graphical analyses of molecular dynamics trajectories, graphical representation of the contribution of active site residues toward the overall binding free energies, free energy profiles with ionized Lys296 residue, charge distribution and geometries during the rate-limiting hydride abstraction step with rasagiline (PDF)

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