Bioassay-guided evaluation of a potent dual inhibitor of host and gut microbial α-glucosidases from Galla chinensis: mechanism insights and in silico studies.

Type 2 diabetes mellitus (T2DM) is characterized by high blood glucose levels and has emerged as an increasing public health burden worldwide. α-Glucosidases from both host and gut microbiota played important roles in digestion of carbohydrate to monosaccharides. Dual inhibition against host and gut microbial α-glucosidases hold great potentials in regulating glucose absorption of T2DM patients. This study aimed to discover a dual inhibitor of both host α-glucosidase (α-Glu) and gut microbial glucosidase (SusB) derived from Bacteroides based on bioassay-guided screening. The results demonstrated that the ethanol extract of Galla chinensis exhibited superior dual inhibition on both α-glucosidases and its major constituent 1,2,3,4,6-O-pentagalloylglucose (PGG) could remarkably inhibit α-Glu and SusB with IC50 values of 0.21 ± 0.01 μM and 13.23 ± 1.00 μM, respectively, while the IC50 values of the positive control (acarbose) on α-Glu and SusB were 430.40 ± 19.56 μM and 0.68 ± 0.05 μM, respectively. Inhibition kinetic analysis revealed that PGG functioned as a non-competitive inhibitor against α-Glu with Ki values of 0.27 ± 0.13 μM, and it acted as competitive inhibitor towards SusB with Ki values of 4.50 ± 0.64 μM. Docking simulations demonstrated that PGG could generate hydrogen bonds with allosteric sites in α-Glu and catalytic residues in SusB, respectively. The binding energies of PGG with α-Glu and SusB were - 7.5 kcal/mol and - 9.3 kcal/mol, while them for acarbose were - 8.2 kcal/mol and - 7.3 kcal/mol, respectively. These findings revealed the potential mechanism of PGG for diabetic therapy through retarding the absorption of carbohydrates.