Biomolecular Interactions and Inhibition Kinetics of Human Soluble Epoxide Hydrolase by Tetrapeptide YMSV

Soluble epoxide hydrolase (sEH) contributes to the pathophysiology of neurodegenerative diseases by decreasing the epoxyeicosatrienoic acids/dihydroeicosatrienoic acids ratio and influencing the anti-inflammatory system. Thus, sEH inhibition reduces systemic inflammation, particularly in the brain. This study investigated sEH inhibition by a tetrapeptide, YMSV, and its mechanism of action. Enzyme inhibition kinetics demonstrated that YMSV is a mixed-competitive inhibitor of sEH, with a half-maximal inhibitory concentration (IC50) of 179.5 ± 0.92 µM. Secondary structural analysis of sEH by circular dichroism showed that YMSV decreased the α-helices by 7.7% and increased the β-sheets and random coils by 11.4% and 22%, respectively. Molecular docking simulation indicated that YMSV formed a hydrogen bond with the Asp333 residue of the hydrolase pocket of sEH in addition to the binding of non-active site residues. The findings provide new insights into the mechanism of sEH inhibition by YMSV and its potential as a peptide-based anti-depressant nutraceutical.