Screening and identification of novel milk-derived α-glucosidase inhibitory peptides: insights from molecular...

Milk-derived α-glucosidase-inhibiting peptides are attracting increasing attention from the scientific community because of their exceptional biological activity and excellent safety profile. However, the differences in inhibitory activity among peptides from various milk protein sources remain unclear. In this study, a novel α-glucosidase inhibitory peptide was screened from milk protein hydrolysates derived from different sources and subsequently validated in vitro.

The results obtained indicate that the peptide fraction derived from bovine casein hydrolyzed by alkaline protease exhibited the strongest enzyme inhibitory effect (IC₅₀ = 0.87 ± 0.02 mg mL^-1). Through mass spectrometry identification combined with molecular docking and molecular dynamics simulations, it was found that the peptide segment FRQFYQL can stably bind to α-glucosidase via hydrogen bonds and hydrophobic interactions (-11.2 kcal mol^-1). The in vitro experiments revealed that the inhibitory activity of this peptide (IC₅₀ = 0.35 ± 0.04 mg mL^-1) was higher than that of the original hydrolysate. Furthermore, FRQFYQL significantly increased glucose absorption and glycogen production in insulin-resistant HepG2 cells. Network pharmacology analysis suggested that FRQFYQL may improve glucose metabolism-related complications by regulating signaling pathways such as TNF and IL-17, thereby reducing cellular glucose levels and pro-inflammatory factor expression.

The peptide FRQFYQL effectively inhibits α-glucosidase activity, and enhances cellular glucose uptake and glycogen synthesis, thus demonstrating potential as a hypoglycemic component in functional foods and nutraceuticals. © 2026 Society of Chemical Industry.