Mechanistic Insights into Pancreatic Lipase Inhibition by Pea-Derived Peptides: Integrating Process Optimization, Activity Assays, Docking, and Molecular Dynamics

Pancreatic lipase (PL) plays a central role in dietary lipid digestion and is a promising target for food-derived inhibitors. In this study, pea protein hydrolysates (PPHs) with PL inhibitory activity were prepared by enzymatic hydrolysis and characterized for their functional and peptidomic properties. Compared with pea protein isolate, PPH showed lower surface hydrophobicity, and moderate antioxidant activity. Peptidomic analysis identified 1740 peptides in the active hydrolysate. Combined in silico screening and in vitro validation further identified three peptides, GFSL, WFE, and FGF, as effective PL inhibitors, with IC50 values of 337.81 ± 17.32, 473.32 ± 19.61, and 689.45 ± 39.32 μM, respectively. Molecular simulations indicated that these peptides interact with the catalytic pocket of PL mainly through hydrophobic interactions, van der Waals forces, and hydrogen bonding, with Ile79 serving as a key residue for peptide recognition. Overall, these findings indicate the potential of pea-derived peptides as natural PL inhibitors and support their application as functional food ingredients for modulating lipid digestion.