Study of polyphenols from Caesalpinia paraguariensis as α-glucosidase inhibitors: kinetics and structure–activity relationship

• Published in: New journal of chemistry 2022-06, Vol.46 (23), p.11044-11055
• Main Authors: Sgariglia, Melina A., Garibotto, Francisco M., Soberón, José R., Angelina, Emilio L., Andujar, Sebastián A., Vattuone, Marta A.
• Format: Article
• Language: English
• Subjects: Bark; Binding sites; Glucosidase; Homology; Inhibitors; Molecular docking; Molecular dynamics; Molecular interactions; Polyphenols; Quantum theory
• ISSN: 1144-0546; 1369-9261
• DOI: 10.1039/D1NJ04619E

Five polyphenolic derivatives isolated from a bioactive fraction of Caesalpinia paraguariensis bark were identified as (1) ellagic acid, (2) 3- O -methylellagic, (3) 3,3′- O -dimethylellagic acid, (4) 3,3′- O -dimethylellagic-4- O -β- d -xylopyranoside and (5) (−)epigallocatechin-gallate. The yeast α-glucosidase (α-Glu) inhibitory activity was evaluated in vitro , including acarbose and luteolin as positive controls. Compound 5 showed significantly more inhibitory activity (IC 50 5.20 μM) than the ellagic derivatives (IC 50 65–263 μM). Compounds 3 and 5 showed non-competitive inhibition ( K i 50.0 and 7.8 μM, respectively); ellagic xyloside (4) showed competitive inhibition ( K i 17.5 μM); and ellagic acid (1) and 3- O -methylellagic (2) showed mixed-type inhibition ( K i 68.3 and 6.0 μM, respectively). Computational studies considering the experimental kinetic constants were performed by homology modelling and molecular docking to predict the binding mode of the compounds. Subsequently, a detailed analysis of the molecular interactions at the α-Glu active site was performed by molecular dynamic simulations and quantum theory of atoms in molecules (MD/QTAIM). While some expected relationships between structural and activity data were verified, a more general structure–activity relationship could not be derived because of the different types of inhibition exerted by the compounds. Therefore, we propose an alternative binding site for non-competitive inhibitors that along with active site binding provides a more comprehensive picture of the inhibition event.