%0 Journal Article
%T Discovery and characterization of small-molecule TGR5 ligands with agonistic activity.
%A Papadopoulos MGE
%A Perhal AF
%A Medel-Lacruz B
%A Ladurner A
%A Selent J
%A Dirsch VM
%A Kolb P
%J Eur J Med Chem
%V 276
%N 0
%D 2024 Oct 5
%M 38996653
%F 7.088
%R 10.1016/j.ejmech.2024.116616
%X 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.