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Background: Non-alcoholic fatty liver disease (NAFLD) is a global health concern affecting an estimated 25% of the population in some regions. The Farnesoid X receptor (FXR) has emerged as a promising therapeutic target for NAFLD, but current FXR agonists have limitations. This study aimed to design new non-bile acid FXR agonists with improved physicochemical and pharmacokinetics properties using structure-based drug design. Methods: X-ray crystal structures of the human FXR ligand binding domain were obtained and prepared for docking studies. A library of 400 small molecule compounds was designed based on bioisosteric replacements of known FXR agonists and optimization of pharmacokinetic parameters. Molecular docking was performed using Autodock VINA GPU 2.0. Results: From 286 virtual analogues of the native FXR agonist GW4064, several key structure-activity relationships were identified. Among the top-ranking compounds, LIG-2, showed a predicted binding energy of −11.9 kcal/mol, compared to −11.3 kcal/mol for AWL. LIG-2 featured strategic fluorination and trifluoromethyl groups, resulting in improved predicted binding affinity and physicochemical properties. Further modifications of LIG-2 led to 15 derivatives, with LIG-2A demonstrating the highest predicted binding affinity (−12.3 kcal/mol). This study successfully identified novel FXR agonists with improved predicted binding affinities and optimised drug-like properties through computational methods. The modifications, particularly the introduction of fluorine atoms and trifluoromethyl groups, showed promise in enhancing both binding affinity and key physicochemical properties. However, challenges remain in improving oral bioavailability and solubility. These findings provide a foundation for further optimization and experimental testing of potential FXR agonists for NAFLD treatment.

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Structure-Based Design of Novel Farnesoid X Receptor Agonists for Non-Alcoholic Fatty Liver Disease Treatment

  • 会议论文

  • 发表日期：

    2026年

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  • Sajda Eltaj M. Adam,
  • Salah A. Alshehade,
  • Ahmad Naoras Bitar,
  • Kesevan Rajah Kumaran,
  • Tahani Al-Shangeeti,
  • Mohamad Dayoob,
  • Tay Hui Yi,
  • Low Xin Leng,
  • Safni Safni

摘要

Background: Non-alcoholic fatty liver disease (NAFLD) is a global health concern affecting an estimated 25% of the population in some regions. The Farnesoid X receptor (FXR) has emerged as a promising therapeutic target for NAFLD, but current FXR agonists have limitations. This study aimed to design new non-bile acid FXR agonists with improved physicochemical and pharmacokinetics properties using structure-based drug design. Methods: X-ray crystal structures of the human FXR ligand binding domain were obtained and prepared for docking studies. A library of 400 small molecule compounds was designed based on bioisosteric replacements of known FXR agonists and optimization of pharmacokinetic parameters. Molecular docking was performed using Autodock VINA GPU 2.0. Results: From 286 virtual analogues of the native FXR agonist GW4064, several key structure-activity relationships were identified. Among the top-ranking compounds, LIG-2, showed a predicted binding energy of −11.9 kcal/mol, compared to −11.3 kcal/mol for AWL. LIG-2 featured strategic fluorination and trifluoromethyl groups, resulting in improved predicted binding affinity and physicochemical properties. Further modifications of LIG-2 led to 15 derivatives, with LIG-2A demonstrating the highest predicted binding affinity (−12.3 kcal/mol). This study successfully identified novel FXR agonists with improved predicted binding affinities and optimised drug-like properties through computational methods. The modifications, particularly the introduction of fluorine atoms and trifluoromethyl groups, showed promise in enhancing both binding affinity and key physicochemical properties. However, challenges remain in improving oral bioavailability and solubility. These findings provide a foundation for further optimization and experimental testing of potential FXR agonists for NAFLD treatment.