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.
| Original language | English |
|---|---|
| Article number | 116616 |
| Journal | European Journal of Medicinal Chemistry |
| Volume | 276 |
| DOIs | |
| Publication status | Published - 5 Oct 2024 |
Funding
M.G.E.P., J.S. and P.K. were members of COST Action CA18133 \u201CERNEST\u201D (European Research NEtwork on Signal Transduction). M.G.E.P. thanks \u201CERNEST\u201D for receiving STSM 48629. We would like to thank Marcel G\u00FChner, Maria-Rosa Krois, Marvin Csar, and Dominik D. Burkhard for their support in performing the biological assays, as well as David Aranda and Karin Zipse for contributing to the computational analyses. We would like to thank Ammar Tahir and Christina Sykora for identity and purity testing of compounds, and Prof. Quitterer for providing the stable HEK EPAC cell line for experiments. Frank Balzer is acknowledged for maintaining the computational infrastructure in the Kolb lab. P.K. thanks the German Research Foundation DFG for Heisenberg Professorship KO4095/5-1. M.G.E.P. J.S. and P.K. were members of COST Action CA18133 \u201CERNEST\u201D (European Research NEtwork on Signal Transduction). M.G.E.P. thanks \u201CERNEST\u201D for receiving STSM 48629. We would like to thank Marcel G\u00FChner, Maria-Rosa Krois, Marvin Csar, and Dominik D. Burkhard for their support in performing the biological assays, as well as David Aranda and Karin Zipse for contributing to the computational analyses. We would like to thank Ammar Tahir and Christina Sykora for identity and purity testing of compounds, and Prof. Quitterer for providing the stable HEK EPAC cell line for experiments. Frank Balzer is acknowledged for maintaining the computational infrastructure in the Kolb lab. P.K. thanks the German Research Foundation DFG for Heisenberg Professorship KO4095/5\u20131.
Austrian Fields of Science 2012
- 301209 Pharmacy
Keywords
- CRE-Luciferase assay
- Molecular docking
- Molecular dynamics simulations
- PAM
- Structure-based drug design
- TGR5
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