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Inhibitory effect of α-ketoglutaric acid on α-glucosidase: integrating molecular dynamics simulation and inhibition kinetics.
- Source :
-
Journal of biomolecular structure & dynamics [J Biomol Struct Dyn] 2020 Aug; Vol. 38 (12), pp. 3496-3503. Date of Electronic Publication: 2019 Sep 09. - Publication Year :
- 2020
-
Abstract
- The inhibition of α-glucosidase is used as a key clinical approach to treat type 2 diabetes mellitus and thus, we assessed the inhibitory effect of α-ketoglutaric acid (AKG) on α-glucosidase with both an enzyme kinetic assay and computational simulations. AKG bound to the active site and interacted with several key residues, including ASP68, PHE157, PHE177, PHE311, ARG312, TYR313, ASN412, ILE434 and ARG439, as detected by protein-ligand docking and molecular dynamics simulations. Subsequently, we confirmed the action of AKG on α-glucosidase as mixed-type inhibition with reversible and rapid binding. The relevant kinetic parameter IC <subscript>50</subscript> was measured (IC <subscript>50</subscript> = 1.738 ± 0.041 mM), and the dissociation constant was determined ( K <subscript>i Slope</subscript> = 0.46 ± 0.04 mM). Regarding the relationship between structure and activity, a high AKG concentration induced the slight modulation of the shape of the active site, as monitored by hydrophobic exposure. This tertiary conformational change was linked to AKG inhibition and mostly involved regional changes in the active site. Our study provides insight into the functional role of AKG due to its structural property of a hydroxyphenyl ring that interacts with the active site. We suggest that similar hydroxyphenyl ring-containing compounds targeting key residues in the active site might be potential α-glucosidase inhibitors. AbbreviationsAKGalpha-ketoglutaric acidpNPG4-nitrophenyl-α-d-glucopyranosideANS1-anilinonaphthalene-8-sulfonateMDmolecular dynamics.Communicated by Ramaswamy H. Sarma.
Details
- Language :
- English
- ISSN :
- 1538-0254
- Volume :
- 38
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Journal of biomolecular structure & dynamics
- Publication Type :
- Academic Journal
- Accession number :
- 31448679
- Full Text :
- https://doi.org/10.1080/07391102.2019.1659858