Molecular Docking Studies and In Vitro Activity of Pancreatic Lipase Inhibitors from Yak Milk Cheese.

Pancreatic lipase serves as a primary trigger for hyperlipidemia and is also a crucial target in the inhibition of hypercholesterolemia. By synthesizing anti-hypercholesterolemic drugs such as atorvastatin, which are used to treat hypercholesterolemia, there were some side effects associated with the long-term use of statins. Based on this idea, in the present study, we identified peptides that inhibited PL by virtual screening and in vitro activity assays. In addition, to delve into the underlying mechanisms, we undertook a dual investigative approach involving both molecular docking analyses and molecular dynamics simulations. The results showed that peptides RK7, KQ7, and TL9, all with molecular weights of <1000 Da and a high proportion of hydrophobic amino acids, inhibited PL well. Molecular docking and molecular dynamics showed that peptides RK7, KQ7, and TL9 bound to important amino acid residues of PL, such as Pro and Leu, through hydrogen bonding, hydrophobic interactions, salt bridges, and π-π stacking to occupy the substrate-binding site, which inhibited PL and identified them as potential PL inhibitors. In vitro tests showed that the IC50 of RK7 and KQ7 on PL were 0.690 mg/mL and 0.593 mg/mL, respectively, and the inhibitory effects of RK7 and KQ7 on PL were significantly enhanced after simulated gastrointestinal digestion. Our results suggested that peptides RK7 and KQ7 from yak milk cheese can be identified as a novel class of potential PL inhibitors.