Summary: | Flavonoids and triterpenoids were revealed to be the potential inhibitors on soluble epoxide hydrolase (sEH). The aim of this study is to reveal sEH inhibitors from Fuji apples. A flavonoid and three triterpenoids derived from the fruit of <i>Malus domestica</i> were identified as quercetin-3-<i>O</i>-arabinoside (<b>1</b>), ursolic acid (<b>2</b>), corosolic acid (<b>3</b>), and 2-oxopomolic acid (<b>4</b>). They had half-maximal inhibitory concentration of the inhibitors (IC<sub>50</sub>) values of 39.3 ± 3.4, 84.5 ± 9.5, 51.3 ± 4.9, and 11.4 ± 2.7 μM, respectively, on sEH. The inhibitors bound to allosteric sites of enzymes in mixed (<b>1</b>) and noncompetitive modes (<b>2</b>–<b>4</b>). Molecular simulations were carried out for inhibitors <b>1</b> and <b>4</b> to calculate the binding force of ligands to receptors. The inhibitors bound to the left (<b>1</b>) and right (<b>4</b>) pockets next to the enzyme’s active site. Based on analyses of their molecular docking and dynamics, it was shown that inhibitors <b>1</b> and <b>4</b> can stably bind sEH at 1 bar and 300 K. Finally, inhibitors <b>1</b> and <b>4</b> are promising candidates for further studies using cell-based assays and in vivo cardiovascular tests.
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