G protein-coupled receptors (GPCRs) play critical roles in human physiology and disease and are one of the most important targets for marketed drugs. GPCR ligands can bind to the orthosteric binding site of the receptor, as well as various topographically distinct allosteric sites, to modulate GPCR activity and downstream signaling cascades. Furthermore, GPCRs can couple to diverse intracellular proteins or form homo- or heterodimers in specific cellular contexts, adding complexity to their signaling behavior. Thus, much of the current GPCR research is aimed at discovering ligands that address the different binding sites and structural organization of GPCRs to develop more specific and safer therapeutics, as well as new pharmacological tools for studying GPCR function and biology. However, there are many problems associated with ligand discovery, highlighting the need to create novel strategies and tools for ligand design, development, and their pharmacological characterization.
This Research Topic aims to highlight advances in the current strategies to identify, develop, and characterize GPCR modulators. Because of the diversity of GPCRs and their ligands, this collection of articles will not be limited to a specific type of modulator but instead cover the entire range of ligands. This encompasses everything from endogenous or synthetic ligands to small molecules, peptides and proteins. Novel ligands with previously unknown binding sites or an interesting pharmacological behavior will be regarded as well as previously known ligands that are further developed or characterized.
In addition, we welcome articles on novel pharmacological tools to investigate the properties and action of ligands, such as fluorescent probes. However, not only the ligands themselves should be highlighted but also the strategies by which they were derived. These could be computational as well as experimental and may include novel experimental technologies as well as in silico prediction methods that have so far not been confirmed in vitro. Thus, the Research Topic will be a collection and resource for all kinds of GPCR ligands as well as strategies to discover them.
We are interested in all types of accepted manuscripts that address, but are not limited to, the following areas:
- Novel findings of known or previously found GPCR ligands;
- Synthesis and characterization of GPCR ligands;
- Structure-based prediction of GPCR ligands;
- Machine learning tools in GPCR ligand discovery;
- Computational, biophysical, and/or chemical-based approaches to identify GPCR ligands;
- Development and application of DNA-encoded chemical libraries for GPCR drug discovery;
- Analysis of structure-activity relationships to elucidate crucial ligand features;
- Discovery, development, and characterization of endogenous or synthetic GPCR ligands;
- Discovery, development, and characterization of small molecule, peptide or protein GPCR ligands;
- Design, synthesis, and evaluation of novel GPCR pharmacological tools (covalent or fluorescent probes, PET tracers…);
- Discovery, development, and characterization of allosteric, bitopic, dual, bivalent or biased GPCR ligands.
This Research Topic is hosted in collaboration with the 2nd Transatlantic Early Career Investigators GPCR Symposium