Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies
Cholestasis is a common clinical disease caused by a disorder in bile acids (BAs) homeostasis, which promotes its development. The Farnesoid X receptor (FXR) plays a critical role in regulating BAs homeostasis, making it an essential target for cholestasis treatment. Although several active FXR agon...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2023-06-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2023.1197856/full |
| _version_ | 1797803829493760000 |
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| author | Lili Xi Axi Shi Tiantian Shen Guoxu Wang Yuhui Wei Jingjing Guo |
| author_facet | Lili Xi Axi Shi Tiantian Shen Guoxu Wang Yuhui Wei Jingjing Guo |
| author_sort | Lili Xi |
| collection | DOAJ |
| description | Cholestasis is a common clinical disease caused by a disorder in bile acids (BAs) homeostasis, which promotes its development. The Farnesoid X receptor (FXR) plays a critical role in regulating BAs homeostasis, making it an essential target for cholestasis treatment. Although several active FXR agonists have been identified, effective drugs for cholestasis are still lacking. To address this, a molecular docking-based virtual screening method was used to identify potential FXR agonists. A hierarchical screening strategy was employed to improve the screening accuracy, and six compounds were selected for further evaluation. Dual-luciferase reporter gene assay was used to demonstrate FXR activation by the screened compounds, and their cytotoxicity was then evaluated. Among the compounds, licraside showed the best performance and was selected for in vivo evaluation using an ANIT-induced cholestasis animal model. Results demonstrated that licraside significantly reduced biliary TBA, serum ALT, AST, GGT, ALP, TBIL, and TBA levels. Liver histopathological analysis showed that licraside also had a therapeutic effect on ANIT-induced liver injury. Overall, these findings suggest that licraside is an FXR agonist with potential therapeutic effects on cholestasis. This study provides valuable insights into the development of novel lead compounds from traditional Chinese medicine for cholestasis treatment. |
| first_indexed | 2024-03-13T05:26:55Z |
| format | Article |
| id | doaj.art-e7e9b46993354ce39886052ae04d740b |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-03-13T05:26:55Z |
| publishDate | 2023-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-e7e9b46993354ce39886052ae04d740b2023-06-15T05:33:28ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122023-06-011410.3389/fphar.2023.11978561197856Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studiesLili Xi0Axi Shi1Tiantian Shen2Guoxu Wang3Yuhui Wei4Jingjing Guo5Office of Institution of Drug Clinical Trial, The First Hospital of Lanzhou University, Lanzhou, ChinaDepartment of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, ChinaThe First School of Clinical Medicine, Lanzhou University, Lanzhou, ChinaSchool of Pharmacy, Lanzhou University, Lanzhou, ChinaDepartment of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, ChinaCentre in Artificial Intelligence Driven Drug Discovery, Faculty of Applied Sciences, Macao Polytechnic University, Macao, ChinaCholestasis is a common clinical disease caused by a disorder in bile acids (BAs) homeostasis, which promotes its development. The Farnesoid X receptor (FXR) plays a critical role in regulating BAs homeostasis, making it an essential target for cholestasis treatment. Although several active FXR agonists have been identified, effective drugs for cholestasis are still lacking. To address this, a molecular docking-based virtual screening method was used to identify potential FXR agonists. A hierarchical screening strategy was employed to improve the screening accuracy, and six compounds were selected for further evaluation. Dual-luciferase reporter gene assay was used to demonstrate FXR activation by the screened compounds, and their cytotoxicity was then evaluated. Among the compounds, licraside showed the best performance and was selected for in vivo evaluation using an ANIT-induced cholestasis animal model. Results demonstrated that licraside significantly reduced biliary TBA, serum ALT, AST, GGT, ALP, TBIL, and TBA levels. Liver histopathological analysis showed that licraside also had a therapeutic effect on ANIT-induced liver injury. Overall, these findings suggest that licraside is an FXR agonist with potential therapeutic effects on cholestasis. This study provides valuable insights into the development of novel lead compounds from traditional Chinese medicine for cholestasis treatment.https://www.frontiersin.org/articles/10.3389/fphar.2023.1197856/fullFXRlicrasideagonistcholestasisvirtual screeningbiological evaluation |
| spellingShingle | Lili Xi Axi Shi Tiantian Shen Guoxu Wang Yuhui Wei Jingjing Guo Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies Frontiers in Pharmacology FXR licraside agonist cholestasis virtual screening biological evaluation |
| title | Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies |
| title_full | Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies |
| title_fullStr | Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies |
| title_full_unstemmed | Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies |
| title_short | Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies |
| title_sort | licraside as novel potent fxr agonist for relieving cholestasis structure based drug discovery and biological evaluation studies |
| topic | FXR licraside agonist cholestasis virtual screening biological evaluation |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2023.1197856/full |
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