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

• Main Authors: Shao-Rong Wang, Tingting Xu, Kai Deng, Chi-Wai Wong, Jinsong Liu, Wei-Shuo Fang
• Format: Article
• Language: English
• Published: MDPI AG 2017-04-01
• Series: Molecules
• Subjects: FXR antagonist; oleanolic acid; compound diversity; library design; molecular modeling
• Online Access: http://www.mdpi.com/1420-3049/22/5/690

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.