Title: Protostane-type triterpenoids as natural soluble epoxide hydrolase inhibitors: Inhibition potentials and molecular dynamics.

Authors: Sun, Cheng-Peng; Zhang, Juan; Zhao, Wen-Yu; Yi, Jing; Yan, Jian-Kun; Wang, Ya-Li; Morisseau, Christophe; Liu, Zhong-Bo; Hammock, Bruce D; Ma, Xiao-Chi

Published In Bioorg Chem, (2020 03)

Abstract: The inhibition of soluble epoxide hydrolase (sEH) is a promising therapeutic approach to treat inflammation and other disorders. In our present investigation on searching for sEH inhibitors from traditional Chinese medicines, we found that Alisma orientale displayed inhibition of sEH. We constructed a small library of protostane-type triterpenoids (1-25) isolated from A. orientale, and screened their inhibitory activities. Alismanin B (1), 11-deoxy-25-anhydro alisol E (4), 11-deoxy alisol B (5), and 25-O-ethyl alisol A (15) displayed concentration-dependently inhibitory activities against sEH with IC50 values from 3.40 ± 0.57 μM to 9.57 ± 0.88 μM. 11-Deoxy-25-anhydro alisol E (4) and 11-deoxy alisol B (5) were defined as mixed-type competitive inhibitors with Ki values of 12.6 and 3.48 μM, respectively, based on the result of inhibition kinetics. The potential interaction mechanism of 11-deoxy alisol B (5) with sEH was analyzed by molecular docking and molecular dynamics, revealing that amino acid residues Trp336 and Tyr466 were vital for its inhibitory activity.

PubMed ID: 32032849

MeSH Terms: Alisma/chemistry*; Enzyme Inhibitors/chemistry*; Enzyme Inhibitors/isolation & purification; Enzyme Inhibitors/pharmacology*; Epoxide Hydrolases/antagonists & inhibitors*; Epoxide Hydrolases/metabolism; Humans; Molecular Docking Simulation; Molecular Dynamics Simulation; Triterpenes/chemistry*; Triterpenes/isolation & purification; Triterpenes/pharmacology*