Screening, Identification and Mechanism of Action of Cod-Derived Soluble Epoxide Hydrolase Inhibitory Peptides Based on Pharmacophore Model

The physiological inhibitors of soluble epoxide hydrolase (sEH) have significant efficacy in the treatment of hypertension, inflammation, cardiovascular disease and diabetes. In this study, a Hypogen pharmacophore was developed using Atlantic cod peptide and was used to screen for bioactive peptides with tryptophan and sEH inhibitory activity by molecular docking. Bioactive peptide sequences were prepared by solid-phase synthesis, and their in vitro sEH inhibitory activity was determined by high performance liquid chromatography (HPLC). The results showed that the tetrapeptide (PLLW) selected by the optimal pharmacophore model had the best Fit value (9.053) and LibDock score (147.807), and its half-maximal inhibitory concentration (IC₅₀) was 506.66 μmol/L. The molecular docking results showed that PLLW competed with physiological substrates to bind to the active site of sEH through hydrogen bonding and hydrophobic interactions. This study provides a new idea for the screening and mechanistic study of sEH inhibitors in foodborne mixed systems, and also provides a suitable model for the development of sEH inhibitor products.