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Structural Insight into the Binding Mode of FXR and GPBAR1 Modulators

Francesco Saverio Di Leva1, Daniele Di Marino2,3, Vittorio Limongelli4,5

  • 1Department of Pharmacy, University of Naples "Federico II", Naples, Italy.

Handbook of Experimental Pharmacology
|June 5, 2019
PubMed

Insights

This chapter details how bile acids and other molecules bind to FXR and GPBAR1 receptors, crucial targets for treating lipid and glucose disorders. Understanding these interactions aids in designing new drugs for metabolic diseases.

Area of Science:

  • Biochemistry and Molecular Pharmacology
  • Metabolic Disease Research

Background:

  • Nuclear farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1) are key regulators of lipid and glucose homeostasis.
  • Dysregulation of FXR and GPBAR1 signaling is implicated in various metabolic disorders, making them attractive therapeutic targets.

Purpose of the Study:

  • To provide a comprehensive review of the binding modes of bile acid (BA) and non-BA ligands to FXR and GPBAR1.
  • To elucidate the chemical and structural determinants governing ligand-receptor interactions.
  • To offer guidelines for designing ligands with selective or dual activity for future drug discovery.

Main Methods:

  • Review of existing literature on ligand-FXR and ligand-GPBAR1 interactions.
  • Analysis of structural and chemical features of known ligands.
  • Comparative analysis of binding modes across different ligand classes.

Main Results:

  • Detailed characterization of diverse binding modes for bile acid and non-bile acid ligands.
  • Identification of key chemical and structural features influencing ligand affinity and efficacy.
  • Insights into achieving receptor selectivity or dual agonism through ligand design.

Conclusions:

  • Understanding ligand-receptor interactions is critical for targeting FXR and GPBAR1.
  • This knowledge provides a foundation for rational drug design of novel therapeutics for metabolic diseases.
  • Future research can leverage these findings to develop selective modulators for improved patient outcomes.
Keywords:
Bile acidsFXRGPBAR1Homology modellingMolecular dockingMolecular dynamics (MD)X-ray crystallography

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