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Molecules 2017, 22(5), 690; doi:10.3390/molecules22050690

Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods

1
State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, 2A Nanwei Road, Beijing 100050, China
2
Center for Drug Evaluation, China Food and Drug Administration, 1A Fuxing Road, Beijing 100038, China
3
School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
4
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
5
NeuMed Pharmaceuticals Limited, Unit 509, 5/F BioTech Center I, No. 9 Science Park West Avenue, Shatin, Hong Kong, China
These authors contributed equally to this paper.
*
Author to whom correspondence should be addressed.
Academic Editor: Diego Muñoz-Torrero
Received: 15 March 2017 / Revised: 13 April 2017 / Accepted: 21 April 2017 / Published: 26 April 2017
(This article belongs to the Section Medicinal Chemistry)
View Full-Text   |   Download PDF [1787 KB, uploaded 26 April 2017]   |  

Abstract

The pentacyclic triterpene oleanolic acid (OA, 1) with known farnesoid X receptor (FXR) modulatory activity was modified at its C-3 position to find new FXR-interacting agents. A diverse substitution library of OA derivatives was constructed in silico through a 2D fingerprint similarity cluster strategy. With further docking analysis, four top-scored OA 3-O-ester derivatives were selected for synthesis. The bioassay results indicated that all four compounds 3 inhibited chenodeoxycholic acid (CDCA)-induced FXR transactivation in a concentration-dependent mode. Among them 3b and 3d are more active than the parent compound OA. A molecular simulation study was performed to attempt to explain the structure-activity relationship (SAR) and the antagonistic action. To the best of our knowledge, this is the first report on semi-synthetic pentacyclic triterpenoids with FXR-modulatory activities. View Full-Text
Keywords: FXR antagonist; oleanolic acid; compound diversity; library design; molecular modeling FXR antagonist; oleanolic acid; compound diversity; library design; molecular modeling
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Wang, S.-R.; Xu, T.; Deng, K.; Wong, C.-W.; Liu, J.; Fang, W.-S. Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods. Molecules 2017, 22, 690.

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