Inhibitory Effect of Polyphenols from the Whole Green Jackfruit Flour against α-Glucosidase, α-Amylase, Aldose Reductase and Glycation at Multiple Stages and Their Interaction: Inhibition Kinetics and Molecular Simulations

Abstract

For the first time, α-glucosidase, α-amylase, aldose reductase, and glycation at multiple stages inhibitory assays were used to explore the antidiabetic potential of whole unripe jackfruit (peel with pulp, flake, and seed). Two polyphenols (phenolic acids) with strong antihyperglycaemic activity were isolated from the methanol extract of whole jackfruit flour (MJ) using activity-guided repeated fractionation on a silica gel column chromatography. The bioactive compounds isolated were identified as 3-(3,4-Dihydroxyphenyl)-2-propenoic acid (caffeic acid: CA) and 4-Hydroxy-3,5-dimethoxybenzoic acid (syringic acid: SA) after various physicochemical and spectroscopic investigations. CA (IC50: 8.0 and 26.90 µg/mL) and SA (IC50: 7.5 and 25.25 µg/mL) were identified to inhibit α-glucosidase and α-amylase in a competitive manner with low Ki values. In vitro glycation experiments further revealed that MJ and its components inhibited each stage of protein glycation as well as the generation of intermediate chemicals. Furthermore, CA (IC50: 3.10) and SA (IC50: 3.0 µg/mL) inhibited aldose reductase effectively in a non-competitive manner, respectively. The binding affinity of these substances towards the enzymes examined has been proposed by molecular docking and molecular dynamics simulation studies, which may explain their inhibitory activities. The found potential of MJ in antihyperglycaemic activity via inhibition of α-glucosidase and in antidiabetic action via inhibition of the polyol pathway and protein glycation is more likely to be related to the presence of the phenolic compounds, according to our findings.

Synthesis, Characterization, Hirshfeld Surface Analysis, Crystal Structure and Molecular Modeling Studies of 1-(4-(Methoxy(phenyl)methyl)-2-methylphenoxy)butan-2-one Derivative as a Novel α-Glucosidase Inhibitor

“…Results obtained from binding free energy calculations support the outcomes of both the docking and the MD simulation in terms of binding efficiency (Table 3). In addition, these outcomes were on par with those in previous studies that performed binding free energy calculations for α-glucosidase [17,18].…”

“…The outcomes from the docking simulation depict that the molecule can bind within the binding site of the enzyme and can induce biological activity, as was observed in the in vitro studies. According to Patil et al [18] and Maradesha et al [17], the docking was accurate, and the binding interactions were similar. The binding interactions validate the results obtained from XRD analysis.…”

“…When compared to the control, this number (IC 50 values) shows the concentration of samples that can inhibit enzyme activity by 50%. The inhibition kinetics of the compound against α-glucosidase was determined using the method described by Maradesha et al [17].…”

“…Protein and ligand preparation was performed according to the previous study conducted by Patil et al [18]. Since the constructed model had already been evaluated in previous work by the authors [17], the same model was used in the present study. The binding site prediction and positioning of the binding pocket was established according to the previous work of the authors [18].…”

Discovery of Novel Coumarin Derivatives as Potential Dual Inhibitors against α-Glucosidase and α-Amylase for the Management of Post-Prandial Hyperglycemia via Molecular Modelling Approaches

“…The drug is known to reduce hyperglycemic levels and is popular among diabetic individuals. It was also used as a positive control in our previous studies [8,22,23]. The biomolecular software package, GROMACS 18.1 was employed to perform molecular dynamics simulations.…”