Journal
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
Volume 183, Issue -, Pages 811-817Publisher
ELSEVIER
DOI: 10.1016/j.ijbiomac.2021.04.187
Keywords
Soluble epoxide hydrolase; Inhibition kinetics; Molecular dynamics simulations
Funding
- National Natural Science Foundation of China [81703679]
- National Key Research and Development Program of China [2018YFC1705900]
- Liaoning Provincial Key Research and Development Program [2019JH2/10300022]
- Natural Science Foundation of Liaoning Province [2020MS256]
- Dalian Young Star of Science and Technology [2019RQ123]
- Liaoning BaiQianWan Talents Program
- Dalian High Level Talents Innovation Support Plan
- Dalian Science and Technology Leading Talents Project [2019RD15]
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The inhibition of soluble epoxide hydrolase (sEH) is considered an effective treatment for inflammation-related diseases. Two novel sEH inhibitors were identified from Alisma orientate, providing potential leads for the development of sEH inhibitors based on protostane-type triterpenoids. In-depth studies revealed the mechanism of inhibition and highlighted the role of amino acid residue Ser374 in the activity of the inhibitors.
Inhibition of soluble epoxide hydrolase (sEH) is considered to be an effective treatment for inflammation-related diseases, and small molecules origin from natural products show promising activity against sEH. Two undescribed protostanes, 3 beta-hydroxy-25-anhydro-alisol F (1) and 3 beta-hydroxy-alisol G (2) were isolated from Alisma orientate and identified as new sEH inhibitors with IC50 values of 10.06 and 30.45 mu M, respectively. Potential lead compound 1 was determined as an uncompetitive inhibitor against sEH, which had a Kj value of 5.13 mu M. In-depth molecular docking and molecular dynamics simulations revealed that amino acid residue Ser374 plays an important role in the inhibition of 1, which also provides an idea for the development of sEH inhibitors based on protostane-type triterpenoids. (C) 2021 Elsevier B.V. All rights reserved.
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