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

  • Eur J Med Chem. 2024 Jun 28:276:116616. doi: 10.1016/j.ejmech.2024.116616.
M Giovanna E Papadopoulos  1 ,  Alexander F Perhal  2 ,  Brian Medel-Lacruz  3 ,  Angela Ladurner  2 ,  Jana Selent  3 ,  Verena M Dirsch  2 ,  Peter Kolb  4
Affiliations
  • 1. Department of Pharmaceutical Chemistry, University of Marburg, Marburg, Germany.
  • 2. Department of Pharmaceutical Sciences, University of Vienna, Vienna, Austria.
  • 3. Research Programme on Biomedical Informatics (GRIB), Department of Experimental and Health Sciences, Hospital del Mar Medical Research Institute (IMIM), Pompeu Fabra University (UPF), Barcelona, Spain.
  • 4. Department of Pharmaceutical Chemistry, University of Marburg, Marburg, Germany. Electronic address: [email protected].
PMID: 38996653 DOI: 10.1016/j.ejmech.2024.116616
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.
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