Trends in GPCR drug discovery: new agents, targets and indications

By Alexander Sebastian Hauser, Misty M. Attwood, M. Rask-Andersen, Helgi B. Schiöth, David E. Gloriam. 2017

2,288 citations recorded by the source corpus.

G protein-coupled receptors (GPCRs) are the most intensively studied drug targets, mostly due to their substantial involvement in human pathophysiology and their pharmacological tractability. Here, we report an up-to-date analysis of all GPCR drugs and agents in clinical trials, which reveals current trends across molecule types, drug targets and therapeutic indications, including showing that 475 drugs (~34% of all drugs approved by the US Food and Drug Administration (FDA)) act at 108 unique GPCRs. Approximately 321 agents are currently in clinical trials, of which ~20% target 66 potentially novel GPCR targets without an approved drug, and the number of biological drugs, allosteric modulators and biased agonists has increased. The major disease indications for GPCR modulators show a shift towards diabetes, obesity and Alzheimer disease, although several central nervous system disorders are also highly represented. The 224 (56%) non-olfactory GPCRs that have not yet been explored in clinical trials have broad untapped therapeutic potential, particularly in genetic and immune system disorders. Finally, we provide an interactive online resource to analyse and infer trends in GPCR drug discovery.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Surgery

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Citations in the corpus

Multi-State Modeling of G-protein Coupled Receptors at Experimental Accuracy (2021, neutral): “Food and Drug Administration (FDA) target GPCRs.(1,13) GPCRs are integral membrane proteins with a common topology that consists of seven transmembrane helices.”
GPCRdb in 2021: integrating GPCR sequence, structure and function (2020, background): “For all human GPCRs lacking a structure, the segments length and residue numbering is curated based on receptors with similar sequence motifs or overall sequence, and species orthologs are aligned by inferring the information from the human reference protein.”
Improving homology modeling from low-sequence identity templates in Rosetta: A case study in GPCRs (2020, background): “Current estimates suggest around 30% of approved drugs act at a GPCR [3].”
Exploring the free-energy landscape of GPCR activation (2018, background): “Therefore, GPCRs are important in understanding molecular determinants of human diseases, emphasized by considering that 40–50% of pharmaceutical drugs target them (2, 3), and more novel therapeutics await discovery as our knowledge of these versatile receptors grows.”
GPCRdb in 2023: state-specific structure models using AlphaFold2 and new ligand resources (2022, background): “This browser contains data for 543 distinct endogenous ligands for 253 human GPCRs, and 157 mouse, rat, or guinea pig receptors.”
AlphaFold2 versus experimental structures: evaluation on G protein-coupled receptors (2022, background): “As such, GPCRs have a rich history as drug targets, which account for nearly one-third of all approved drugs [5].”
Pharmacogenomics of GPCR Drug Targets (2018, neutral): “Thus, GPCRs serve as primary and secondary targets and determine the pharmacological profiles of the responses (Allen and Roth, 2011; Hauser et al., 2017).”
Coevolutionary Analysis of Protein Subfamilies by Sequence Reweighting (2019, background): “, nuclear receptors [22] or G-protein coupled receptors [23], where the focus is often on specific members or sub-group.”
Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors (2019, background): “Cell 179, 895–908, Octo This is an open access article und gaining traction in current clinical trials (Hauser et al., 2017).”
American Gut: an Open Platform for Citizen Science Microbiome Research (2018, neutral): “Manipulating microbial genes that encode enzymes that produce speciﬁc metabolites eliciting host cellular responses could enable new drugs or treatment strategies for many major diseases, including diabetes, obesity, and Alzheimer’s disease: roughly 34% of all marketed drugs target GPCRs (40).”