Inhibitory Activity of Flavonoids, Chrysoeriol and Luteolin-7- O-Glucopyranoside, on Soluble Epoxide Hydrolase from Capsicum chinense

Abstract

: Three flavonoids derived from the leaves of Capsicum chinense Jacq. were identified as chrysoeriol (1), luteolin-7-O-glucopyranoside (2), and isorhamnetin-7-O-glucopyranoside (3). They had IC₅₀ values of 11.6±2.9, 14.4±1.5, and 42.7±3.5 µg/mL against soluble epoxide hydrolase (sEH), respectively. The three inhibitors (1-3) were found to non-competitively bind into the allosteric site of the enzyme with K_i values of 10.5±3.2, 11.9 ±2.8 and 38.0±4.1 µg/mL, respectively. The potential inhibitors 1 and 2 were located at the left edge ofa U-tube shape that contained the enzyme active site. Additionally, we observed changes in several factors involved in the binding of these complexes under 300 K and 1 bar. Finally, it was confirmed that each inhibitor, 1 and 2, could be complexed with sEH by the "induced fit" and "lock-and-key" models.

Keywords: flavonoids; induced fit; lock-and-key; non-competitive mode; soluble epoxide hydrolase.

Figure 1

The structure of flavonoid derivatives (1–3).

Figure 2

Inhibitory activities of inhibitors 1–3 on sEH (A). Lineweaver–Burk plots (B,D) and Dixon plots (E,F) for the inhibition of sEH by 1–3.

Figure 2

Inhibitory activities of inhibitors 1–3 on sEH (A). Lineweaver–Burk plots (B,D) and Dixon plots (E,F) for the inhibition of sEH by 1–3.

Figure 3

Predicted docking poses of 1 (green) and 2 (blue) into sEH (A). The hydrogen bond (B) and π-π interaction (C) of sEH with 1. The hydrogen bond (D) and π-π interaction (E) between sEH and 2.

Figure 3

Predicted docking poses of 1 (green) and 2 (blue) into sEH (A). The hydrogen bond (B) and π-π interaction (C) of sEH with 1. The hydrogen bond (D) and π-π interaction (E) between sEH and 2.

Figure 4

Superpositions of inhibitors 1 (A) and 2 (B) against sEH for 1 ns (red: 0, orange: 1, yellow: 2, green: 3, forest green: 4, cyan: 5, blue: 6, conflower blue: 7, purple: 8,magenta: 9, and black: 10 ns). The potential (C), RMSD (D), and hydrogen bond numbers (E,F) of 1 and 2 with sEH. The distance (G,H) of compounds 1 and 2 with key amino acids, respectively.