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Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study
Natural flavonoids are capable of inhibiting glucosidase activity, so they can be used for treating diabetes mellitus and hypertension. However, molecular-level details of their interactions with glucosidase enzymes remain poorly understood. This paper describes the synthesis and spectral characteri...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Royal Society of Chemistry
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661682/ https://www.ncbi.nlm.nih.gov/pubmed/38020002 http://dx.doi.org/10.1039/d3ra06276g |
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author | Chepeleva, Liudmyla V. Demidov, Oleksii O. Snizhko, Arsenii D. Tarasenko, Dmytro O. Chumak, Andrii Y. Kolomoitsev, Oleksii O. Kotliar, Volodymyr M. Gladkov, Eugene S. Kyrychenko, Alexander Roshal, Alexander D. |
author_facet | Chepeleva, Liudmyla V. Demidov, Oleksii O. Snizhko, Arsenii D. Tarasenko, Dmytro O. Chumak, Andrii Y. Kolomoitsev, Oleksii O. Kotliar, Volodymyr M. Gladkov, Eugene S. Kyrychenko, Alexander Roshal, Alexander D. |
author_sort | Chepeleva, Liudmyla V. |
collection | PubMed |
description | Natural flavonoids are capable of inhibiting glucosidase activity, so they can be used for treating diabetes mellitus and hypertension. However, molecular-level details of their interactions with glucosidase enzymes remain poorly understood. This paper describes the synthesis and spectral characterization of a series of fluorescent flavonols and their interaction with the β-glucosidase enzyme. To tune flavonol–enzyme interaction modes and affinity, we introduced different polar halogen-containing groups or bulky aromatic/alkyl substituents in the peripheral 2-aryl ring of a flavonol moiety. Using fluorescence spectroscopy methods in combination with molecular docking and molecular dynamics simulations, we examined the binding affinity and identified probe binding patterns, which are critical for steric blockage of the key catalytic residues of the enzyme. Using a fluorescent assay, we demonstrated that the binding of flavonol 2e to β-glucosidase decreased its enzymatic activity up to 3.5 times. In addition, our molecular docking and all-atom molecular dynamics simulations suggest that the probe binding is driven by hydrophobic interactions with aromatic Trp and Tyr residues within the catalytic glycone binding pockets of β-glucosidase. Our study provides a new insight into structure–property relations for flavonol–protein interactions, which govern their enzyme binding, and outlines a framework for a rational design of new flavonol-based potent inhibitors for β-glucosidases. |
format | Online Article Text |
id | pubmed-10661682 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
spelling | pubmed-106616822023-11-21 Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study Chepeleva, Liudmyla V. Demidov, Oleksii O. Snizhko, Arsenii D. Tarasenko, Dmytro O. Chumak, Andrii Y. Kolomoitsev, Oleksii O. Kotliar, Volodymyr M. Gladkov, Eugene S. Kyrychenko, Alexander Roshal, Alexander D. RSC Adv Chemistry Natural flavonoids are capable of inhibiting glucosidase activity, so they can be used for treating diabetes mellitus and hypertension. However, molecular-level details of their interactions with glucosidase enzymes remain poorly understood. This paper describes the synthesis and spectral characterization of a series of fluorescent flavonols and their interaction with the β-glucosidase enzyme. To tune flavonol–enzyme interaction modes and affinity, we introduced different polar halogen-containing groups or bulky aromatic/alkyl substituents in the peripheral 2-aryl ring of a flavonol moiety. Using fluorescence spectroscopy methods in combination with molecular docking and molecular dynamics simulations, we examined the binding affinity and identified probe binding patterns, which are critical for steric blockage of the key catalytic residues of the enzyme. Using a fluorescent assay, we demonstrated that the binding of flavonol 2e to β-glucosidase decreased its enzymatic activity up to 3.5 times. In addition, our molecular docking and all-atom molecular dynamics simulations suggest that the probe binding is driven by hydrophobic interactions with aromatic Trp and Tyr residues within the catalytic glycone binding pockets of β-glucosidase. Our study provides a new insight into structure–property relations for flavonol–protein interactions, which govern their enzyme binding, and outlines a framework for a rational design of new flavonol-based potent inhibitors for β-glucosidases. The Royal Society of Chemistry 2023-11-21 /pmc/articles/PMC10661682/ /pubmed/38020002 http://dx.doi.org/10.1039/d3ra06276g Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/ |
spellingShingle | Chemistry Chepeleva, Liudmyla V. Demidov, Oleksii O. Snizhko, Arsenii D. Tarasenko, Dmytro O. Chumak, Andrii Y. Kolomoitsev, Oleksii O. Kotliar, Volodymyr M. Gladkov, Eugene S. Kyrychenko, Alexander Roshal, Alexander D. Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study |
title | Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study |
title_full | Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study |
title_fullStr | Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study |
title_full_unstemmed | Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study |
title_short | Binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study |
title_sort | binding interactions of hydrophobically-modified flavonols with β-glucosidase: fluorescence spectroscopy and molecular modelling study |
topic | Chemistry |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10661682/ https://www.ncbi.nlm.nih.gov/pubmed/38020002 http://dx.doi.org/10.1039/d3ra06276g |
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