Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods
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 stra...
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MDPI AG
2017-04-01
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| Series: | Molecules |
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| Online Access: | http://www.mdpi.com/1420-3049/22/5/690 |
| _version_ | 1811213484724060160 |
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| author | Shao-Rong Wang Tingting Xu Kai Deng Chi-Wai Wong Jinsong Liu Wei-Shuo Fang |
| author_facet | Shao-Rong Wang Tingting Xu Kai Deng Chi-Wai Wong Jinsong Liu Wei-Shuo Fang |
| author_sort | Shao-Rong Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T05:47:32Z |
| format | Article |
| id | doaj.art-387db5f490be4636abbe525f11f6df2e |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-04-12T05:47:32Z |
| publishDate | 2017-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-387db5f490be4636abbe525f11f6df2e2022-12-22T03:45:24ZengMDPI AGMolecules1420-30492017-04-0122569010.3390/molecules22050690molecules22050690Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking MethodsShao-Rong Wang0Tingting Xu1Kai Deng2Chi-Wai Wong3Jinsong Liu4Wei-Shuo Fang5State 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, ChinaSchool of Life Sciences, University of Science and Technology of China, Hefei 230026, ChinaState 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, ChinaNeuMed Pharmaceuticals Limited, Unit 509, 5/F BioTech Center I, No. 9 Science Park West Avenue, Shatin, Hong Kong, ChinaState Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, ChinaState 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, ChinaThe 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.http://www.mdpi.com/1420-3049/22/5/690FXR antagonistoleanolic acidcompound diversitylibrary designmolecular modeling |
| spellingShingle | Shao-Rong Wang Tingting Xu Kai Deng Chi-Wai Wong Jinsong Liu Wei-Shuo Fang 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 FXR antagonist oleanolic acid compound diversity library design molecular modeling |
| title | Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods |
| title_full | Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods |
| title_fullStr | Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods |
| title_full_unstemmed | Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods |
| title_short | Discovery of Farnesoid X Receptor Antagonists Based on a Library of Oleanolic Acid 3-O-Esters through Diverse Substituent Design and Molecular Docking Methods |
| title_sort | discovery of farnesoid x receptor antagonists based on a library of oleanolic acid 3 o esters through diverse substituent design and molecular docking methods |
| topic | FXR antagonist oleanolic acid compound diversity library design molecular modeling |
| url | http://www.mdpi.com/1420-3049/22/5/690 |
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