Discovery of new GPCR ligands to illuminate new biology
Open accessAbstract
Although a plurality of drugs target G-protein-coupled receptors (GPCRs), most have emerged from classical medicinal chemistry and pharmacology programs and resemble one another structurally and functionally. Though effective, these drugs are often promiscuous. With the realization that GPCRs signal via multiple pathways, and with the emergence of crystal structures for this family of proteins, there is an opportunity to target GPCRs with new chemotypes and confer new signaling modalities. We consider structure-based and physical screening methods that have led to the discovery of new reagents, focusing particularly on the former. We illustrate their use against previously untargeted or orphan GPCRs, against allosteric sites, and against classical orthosteric sites that selectively activate one downstream pathway over others. The ligands that emerge are often chemically novel, which can lead to new biological effects.
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A handful of GPCRs, mainly biogenic amine, muscarinic and opioid receptors, are the most abundantly targeted receptors for FDA-approved medications.
“A recent analysis indicates, however, that a handful of GPCRs — mainly biogenic amine, muscarinic and opioid receptors — represent the most abundantly targeted receptors for FDA-approved medications53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [54]
The Abstract (page unavailable) says GPCRs are the protein family most frequently targeted by therapeutic drugs, and the paper discusses aminergic, muscarinic and opioid receptors. It does not establish that a handful of receptors in those groups are the most abundantly targeted by FDA-approved medications. (LLM, conf=0.82)
Experimental — accuracy not yet measuredAlterations in GPCR signalling are implicated in the pathogenesis and treatment of many disorders, including neuropsychiatric, immunological, gastrointestinal, cardiac, renal, hormonal and infectious disorders.
“Alterations in GPCR signalling are implicated in the pathogenesis and treatment of neuropsychiatric55, immunological56, gastrointestinal57,58, cardiac59, renal, hormonal, infectious60 and many other disorders53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [54]
The Abstract (page unavailable) describes GPCRs as frequent therapeutic targets, and the sections on maraviroc/CCR5 and biased agonists discuss HIV, psychiatric disorders and heart failure. The passages do not establish the full list of disorder categories—particularly gastrointestinal, renal and hormonal disorders—or the broad claim about their pathogenesis. (LLM, conf=0.84)
Experimental — accuracy not yet measuredGPCRs are the largest family of druggable targets in the human genome, with 20-30% of approved drugs acting on them.
“GPCRs represent the largest family of druggable targets in the human genome9, with between 20% and 30% of approved drugs acting on them53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [54]
GPCRs are membrane-bound cell-surface receptors that transduce signals via heterotrimeric G proteins, arrestins and other cellular transducers.
“GPCRs are membrane-bound, cell-surface receptors that transduce signals via interactions with heterotrimeric G proteins, arrestins and other cellular transducers53,54.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [54]
Slightly more than half of non-olfactory GPCRs have annotated drugs and small molecules targeting them.
“Slightly more than half of the non-olfactory GPCRs have annotated drugs and small molecules targeting them53,54,61; see also TABLE 1.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [54]
The Abstract says GPCRs are frequently targeted by drugs, and the GPCR deorphanization section discusses receptors with known ligands (page numbers unavailable). Neither gives the proportion of non-olfactory GPCRs with annotated drugs or small molecules. Searches for that proportion and for known ligands found no passage establishing 'slightly more than half.' (LLM, conf=0.76)
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- Authors
- Roth, B. L., Irwin, J. J., & Shoichet, B. K.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of California, San Francisco (US)
- Corresponding author
- Roth, Bryan L
- Shoichet, Brian K
- Venue
- Nature Chemical Biology
- Published
- 2017-10-18
- Volume
- 13
- Issue
- 11
- Pages
- 1143-1151
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5835362
- OpenAlex
- W2765958735
- Cited by
- 94
- References
- 108
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 9 · 2020: 14 · 2019: 17 · 2018: 17
- FWCI
- 5.36
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Mental Health (U01MH104974)
- National Institute of General Medical Sciences (R35GM122481)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK116195)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Keywords
- G protein-coupled receptors, GPCR ligands, structure-based drug design, orphan G protein-coupled receptor, biased ligands, orthosteric ligands, biased signaling, chemotypes, GPCR crystal structures
- MeSH terms
- Allosteric Regulation, Allosteric Site, Humans, Ligands, Drug Design, Signal Transduction, Receptors, G-Protein-Coupled, Drug Discovery, Molecular Docking Simulation
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