Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

Chaurasiya, Narayan D.; Midiwo, Jacob; Pandey, Pankaj; Bwire, Regina N.; Doerksen, Robert J.; Muhammad, Ilias; Tekwani, Babu L.

doi:10.3390/molecules25225358

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Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B

Narayan D. Chaurasiya

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Department of Infectious Diseases, Division of Drug Discovery, Southern Research, Birmingham, AL 35205, USA

National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA

Department of Chemistry, University of Nairobi, Nairobi P.O. Box 30197-00100, Kenya

⁴

Department of BioMolecular Sciences, Division of Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA

⁵

Department of pure and applied Chemistry, Masinde Muliro University of Science and Technology, Kakamega P.O. Box 190-50100, Kenya

Authors to whom correspondence should be addressed.

Academic Editor: Valeria Patricia Sülsen

Molecules 2020, 25(22), 5358; https://doi.org/10.3390/molecules25225358

Received: 17 September 2020 / Revised: 31 October 2020 / Accepted: 9 November 2020 / Published: 17 November 2020

(This article belongs to the Special Issue Special Issue in Honor of Professor James D. McChesney on the Occasion of his 80th Birthday)

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Abstract

A set of structurally related O-methylated flavonoid natural products isolated from Senecio roseiflorus (1), Polygonum senegalense (2 and 3), Bhaphia macrocalyx (4), Gardenia ternifolia (5), and Psiadia punctulata (6) plant species were characterized for their interaction with human monoamine oxidases (MAO-A and -B) in vitro. Compounds 1, 2, and 5 showed selective inhibition of MAO-A, while 4 and 6 showed selective inhibition of MAO-B. Compound 3 showed ~2-fold selectivity towards inhibition of MAO-A. Binding of compounds 1–3 and 5 with MAO-A, and compounds 3 and 6 with MAO-B was reversible and not time-independent. The analysis of enzyme-inhibition kinetics suggested a reversible-competitive mechanism for inhibition of MAO-A by 1 and 3, while a partially-reversible mixed-type inhibition by 5. Similarly, enzyme inhibition-kinetics analysis with compounds 3, 4, and 6, suggested a competitive reversible inhibition of MAO-B. The molecular docking study suggested that 1 selectively interacts with the active-site of human MAO-A near N5 of FAD. The calculated binding free energies of the O-methylated flavonoids (1 and 4–6) and chalcones (2 and 3) to MAO-A matched closely with the trend in the experimental IC_50′s. Analysis of the binding free-energies suggested better interaction of 4 and 6 with MAO-B than with MAO-A. The natural O-methylated flavonoid (1) with highly potent inhibition (IC₅₀ 33 nM; Ki 37.9 nM) and >292 fold selectivity against human MAO-A (vs. MAO-B) provides a new drug lead for the treatment of neurological disorders. View Full-Text

Keywords: recombinant monoamine oxidase-A; monoamine oxidase-B; neurological disorder; enzyme kinetics; molecular docking; inhibition activity; flavonoid

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Chaurasiya, N.D.; Midiwo, J.; Pandey, P.; Bwire, R.N.; Doerksen, R.J.; Muhammad, I.; Tekwani, B.L. Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B. Molecules 2020, 25, 5358. https://doi.org/10.3390/molecules25225358

AMA Style

Chaurasiya ND, Midiwo J, Pandey P, Bwire RN, Doerksen RJ, Muhammad I, Tekwani BL. Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B. Molecules. 2020; 25(22):5358. https://doi.org/10.3390/molecules25225358

Chicago/Turabian Style

Chaurasiya, Narayan D., Jacob Midiwo, Pankaj Pandey, Regina N. Bwire, Robert J. Doerksen, Ilias Muhammad, and Babu L. Tekwani. 2020. "Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B" Molecules 25, no. 22: 5358. https://doi.org/10.3390/molecules25225358

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