Natural inhibitor combinations targeting α-amylase and α-Glucosidase: A food-derived strategy for safer type 2 diabetes management

The urgent need for safer alternatives to conventional enzyme inhibitors (e.g., acarbose) in type 2 diabetes mellitus (T2DM) management is consistent with the emerging paradigm favoring natural therapeutics over synthetic drugs. This study systematically evaluates the therapeutic potential of natural plant extracts by identifying synergistic combinations that concurrently inhibit α-amylase and α-glucosidase, two key enzymes in carbohydrate digestion. A preliminary screening of 96 plant materials yielded seven promising candidates, and this study focuses on the combination of epigallocatechin gallate (EGCG) with other bioactive extracts. In vitro enzyme inhibition assays demonstrated that the combination of EGCG and Ampelopsis grossedentata extract (EGCG–AG) exhibited synergistic effects against both α-amylase (CI = 0.72; IC₅₀ = 105.5 μg/mL) and α-glucosidase (CI = 0.95; IC₅₀ = 12.16 μg/mL), indicating enhanced cooperative inhibition of both enzymatic targets. Fluorescence quenching analysis confirmed that the EGCG–AG complex induced maximal quenching rates of 98 % and 99 % for α-amylase and α-glucosidase, respectively. These effects were accompanied by characteristic redshifts of 17 nm and 36 nm in the emission peaks, respectively, suggesting pronounced conformational rearrangements at the enzyme active sites upon binding. Molecular docking analysis identified that dihydromyricetin, the primary bioactive compound in AG, and EGCG bind to distinct sites on the target enzymes, cooperatively inducing conformational changes that enhance inhibition. Compared with conventional chemical modification strategies, this naturally derived combination offers a safer approach for the development of functional foods, nutraceuticals, and specialized dietary formulations. We present a promising food-derived intervention strategy for complementary T2DM management.