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

Abstract

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 (IC₅₀ 5.20 μM) than the ellagic derivatives (IC₅₀ 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.