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
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 pharmac...
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MDPI AG
2020-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/21/17/6151 |
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| author | Tana Tandarić Alja Prah Jernej Stare Janez Mavri Robert Vianello |
| author_facet | Tana Tandarić Alja Prah Jernej Stare Janez Mavri Robert Vianello |
| author_sort | Tana Tandarić |
| collection | DOAJ |
| description | 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 ΔΔ<b><i>G</i></b><sup>‡</sup> = 3.1 kcal mol<sup>−1</sup> is found to be in very good agreement with that from the measured literature <b><i>k</i></b><sub>inact</sub> values that predict a 1.7 kcal mol<sup>−1</sup> 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. |
| first_indexed | 2024-03-10T16:48:46Z |
| format | Article |
| id | doaj.art-693acc386959409b81e2ec7c7e0e89be |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T16:48:46Z |
| publishDate | 2020-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-693acc386959409b81e2ec7c7e0e89be2023-11-20T11:25:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-08-012117615110.3390/ijms21176151Hydride Abstraction as the Rate-Limiting Step of the Irreversible Inhibition of Monoamine Oxidase B by Rasagiline and Selegiline: A Computational Empirical Valence Bond StudyTana Tandarić0Alja Prah1Jernej Stare2Janez Mavri3Robert Vianello4Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička Cesta 54, HR-10000 Zagreb, CroatiaLaboratory for Computational Biochemistry and Drug Design, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, SloveniaLaboratory for Computational Biochemistry and Drug Design, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, SloveniaLaboratory for Computational Biochemistry and Drug Design, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, SloveniaDivision of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička Cesta 54, HR-10000 Zagreb, CroatiaMonoamine 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 ΔΔ<b><i>G</i></b><sup>‡</sup> = 3.1 kcal mol<sup>−1</sup> is found to be in very good agreement with that from the measured literature <b><i>k</i></b><sub>inact</sub> values that predict a 1.7 kcal mol<sup>−1</sup> 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.https://www.mdpi.com/1422-0067/21/17/6151irreversible inhibitionmonoamine oxidasehydride transferantiparkinsonian drugsneurodegenerationflavoenzymes |
| spellingShingle | Tana Tandarić Alja Prah Jernej Stare Janez Mavri Robert Vianello 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 irreversible inhibition monoamine oxidase hydride transfer antiparkinsonian drugs neurodegeneration flavoenzymes |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | irreversible inhibition monoamine oxidase hydride transfer antiparkinsonian drugs neurodegeneration flavoenzymes |
| url | https://www.mdpi.com/1422-0067/21/17/6151 |
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