Journal
BIOORGANIC CHEMISTRY
Volume 96, Issue -, Pages -Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2020.103637
Keywords
Soluble epoxide hydrolase; Protostane-type triterpenoids; Inhibition kinetics; Molecular dynamics stimulation
Funding
- National Natural Science Foundation of China [81703769]
- Revolutionizing Innovative, Visionary Environmental Health Research Program of the National Institutes of Environmental Health Sciences [R35 ES030443-01]
- Superfund Basic Research Program of the National Institutes of Environmental Health Sciences [P42 ES04699]
- Dalian Young Star of Science and Technology
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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 mu M to 9.57 +/- 0.88 mu M. 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 mu M, 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.
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