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Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B
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 oxidas...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697615/ https://www.ncbi.nlm.nih.gov/pubmed/33212830 http://dx.doi.org/10.3390/molecules25225358 |
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author | Chaurasiya, Narayan D. Midiwo, Jacob Pandey, Pankaj Bwire, Regina N. Doerksen, Robert J. Muhammad, Ilias Tekwani, Babu L. |
author_facet | Chaurasiya, Narayan D. Midiwo, Jacob Pandey, Pankaj Bwire, Regina N. Doerksen, Robert J. Muhammad, Ilias Tekwani, Babu L. |
author_sort | Chaurasiya, Narayan D. |
collection | PubMed |
description | 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 (IC(50) 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. |
format | Online Article Text |
id | pubmed-7697615 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-76976152020-11-29 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. Molecules Article 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 (IC(50) 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. MDPI 2020-11-17 /pmc/articles/PMC7697615/ /pubmed/33212830 http://dx.doi.org/10.3390/molecules25225358 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Chaurasiya, Narayan D. Midiwo, Jacob Pandey, Pankaj Bwire, Regina N. Doerksen, Robert J. Muhammad, Ilias Tekwani, Babu L. Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
title | Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
title_full | Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
title_fullStr | Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
title_full_unstemmed | Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
title_short | Selective Interactions of O-Methylated Flavonoid Natural Products with Human Monoamine Oxidase-A and -B |
title_sort | selective interactions of o-methylated flavonoid natural products with human monoamine oxidase-a and -b |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697615/ https://www.ncbi.nlm.nih.gov/pubmed/33212830 http://dx.doi.org/10.3390/molecules25225358 |
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