Natural soluble epoxide hydrolase inhibitors from Inula helenium and their interactions with soluble epoxide hydrolase.

The inhibition of soluble epoxide hydrolase (sEH) is regarded as a promising therapeutic approach to treat inflammation and its related disorders. In present work, we investigated inhibitory effects of forty-nine kinds of traditional Chinese medicines against sEH. Inula helenium showed significant inhibitory effect against sEH, and the extract of I. helenium were isolated to obtain eight compounds, including 4H-tomentosin (1), xanthalongin (2), and linoleic acid (3), 8-hydroxy-9-isobutyryloxy-10(2)-methylbutyrylthymol (4), dehydrocostus lactone (5), alantolactone (6), costunolide (7), and isoalantolactone (8). Among them, 4H-tomentosin (1), xanthalongin (2), and linoleic acid (3) showed significantly inhibitory activities on sEH with half maximal inhibitory concentration (IC₅₀) from 5.88 ± 0.97 μM to 11.63 ± 0.58 μM. The inhibition kinetics suggested that 4H-tomentosin (1) and xanthalongin (2) were mixed-competitive type inhibitors with inhibition constant (Ki) values of 7.02 and 6.57 μM, respectively, and linoleic acid (3) was a competitive type inhibitor with a Ki values of 3.52 μM. The potential interactions of 4H-tomentosin (1), xanthalongin (2), and linoleic acid (3) with sEH were analyzed by molecular docking, which indicated that these bioactive compounds had interactions with key amino acid residues Tyr343, Ile363, Tyr383, and His524.