Papadopoulos, Maria Giovanna EvaPerhal, Alexander F.Medel Lacruz, BrianLadurner, AngelaSelent, JanaDirsch, Verena M.Kolb, Peter2025-05-192025-05-192024Papadopoulos MGE, Perhal AF, Medel-Lacruz B, Ladurner A, Selent J, Dirsch VM, et al. 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.2024.1166160223-5234http://hdl.handle.net/10230/70429The 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.application/pdfeng© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).info:eu-repo/semantics/articlehttp://dx.doi.org/10.1016/j.ejmech.2024.116616CRE-Luciferase assayMolecular dockingMolecular dynamics simulationsPAMStructure-based drug designTGR5info:eu-repo/semantics/openAccess