Discovery and characterization of small-molecule TGR5 ligands with agonistic activity

Eur J Med Chem. 2024 Oct 5:276:116616. doi: 10.1016/j.ejmech.2024.116616. Epub 2024 Jun 28.

Abstract

The Takeda G protein-coupled receptor 5 (TGR5) is activated endogenously by primary and secondary bile acids. This receptor is considered a candidate target for addressing inflammatory and metabolic disorders. We have targeted TGR5 with structure-based methods for ligand finding using the recently solved experimental structures, as well as structures obtained from molecular dynamics simulations. Through addressing the orthosteric as well as a putative allosteric site, we identified agonists and positive allosteric modulators. While the predicted binding locations were not in line with their efficacy, our work contributes activating small-molecule ligands that we have thoroughly characterized in vitro.

Keywords: CRE-Luciferase assay; Molecular docking; Molecular dynamics simulations; PAM; Structure-based drug design; TGR5.

MeSH terms

  • Allosteric Site
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Receptors, G-Protein-Coupled* / agonists
  • Receptors, G-Protein-Coupled* / metabolism
  • Small Molecule Libraries / chemical synthesis
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship

Substances

  • Ligands
  • Receptors, G-Protein-Coupled
  • GPBAR1 protein, human
  • Small Molecule Libraries