Screening and Identification of Novel Soluble Epoxide Hydrolase Inhibitors from Corn Gluten Peptides

Abstract

The objective of this study was to investigate the soluble epoxide hydrolase (sEH) inhibitory properties of corn gluten peptides. In total, 400 dipeptides and 8000 tripeptides were first virtually screened by molecular docking and 30 potential sEH inhibitory peptides were selected. Among them, WEY, WWY, WYW, YFW, and YFY showed the highest sEH inhibitory activities with IC50 values of 55.41 ± 1.55, 68.80 ± 7.72, 70.66 ± 9.90, 96.00 ± 7.5, and 94.06 ± 12.86 μM, respectively. These five peptides all behaved as mixed-type inhibitors and were predicted to form hydrogen bond interactions mainly with Asp333, a key residue located in the catalytic active site of sEH. Moreover, it was found that the corn gluten hydrolysates of Alcalase, Flavourzyme, pepsin and pancreatin all exhibited high sEH inhibitory activities, with IC50 values of 1.07 ± 0.08, 1.19 ± 0.24, and 1.46 ± 0.31 mg/mL, respectively. In addition, the sEH inhibitory peptides WYW, YFW, and YFY were successfully identified from the corn gluten hydrolysates by Alcalase using nano-LC-MS/MS. This study demonstrated the sEH inhibitory capacity of peptides for the first time and corn gluten might be a promising food protein source for discovering novel natural sEH inhibitory peptides.

Biomolecular interactions and inhibition kinetics of human soluble epoxide hydrolase by tetrapeptide YMSV

“…The previous study with corn gluten tripeptide WEY, a mixedcompetitive inhibitor, reported a binding affinity of −10.3024 kcal. mol −1 for the sEH active site (Dang et al, 2022), which was lower that the binding affinities of YMSV from both the active site and blind docking. This implies that YMSV has a lower binding affinity for sEH compared to tripeptides.…”

“…The half maximal inhibitory concentration (IC 50 ) was estimated to be 178.5 ± 0.92 µM. A recent study with corn glutenderived tripeptides WEY, WWY, WYW, YFW and YFY showed lower sEH inhibiting IC 50 values ranging from 55.41 to 96 µM (Dang et al, 2022). The higher YMSV IC 50 value could be attributed to its larger size and length, compared to the tripeptides, as the size of the latter could facilitate binding to sEH, or specific favorable binding conformation.…”

“…The higher YMSV IC 50 value could be attributed to its larger size and length, compared to the tripeptides, as the size of the latter could facilitate binding to sEH, or specific favorable binding conformation. Molecular size plays an important role in sEH inhibition since the narrow cavity of the enzyme active site might limit access to large and bulky inhibitors (Dang et al, 2022). The aromatic amino acid residues can readily participate in hydrogen bonding because of their -OH and -NH functional groups, and as nucleophiles at the enzyme active site (Scheiner et al, 2002).…”

“…The aromatic amino acid residues can readily participate in hydrogen bonding because of their -OH and -NH functional groups, and as nucleophiles at the enzyme active site (Scheiner et al, 2002). The tripeptides containing aromatic residues showed high sEH inhibitory activity up to 70% at 100 µM concentration, especially YFW and YFY, which had the highest IC 50 values (Dang et al, 2022). Notably, the tripeptides have a common aromatic amino acid residue, tyrosine, as YMSV, suggesting a similarity in their interactions with sEH.…”