The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
In silico design of novel probes for the atypical opioid receptor MRGPRX2
Open accessAbstract
The primate-exclusive MRGPRX2 G protein-coupled receptor (GPCR) has been suggested to modulate pain and itch. Despite putative peptide and small-molecule MRGPRX2 agonists, selective nanomolar-potency probes have not yet been reported. To identify a MRGPRX2 probe, we first screened 5,695 small molecules and found that many opioid compounds activated MRGPRX2, including (-)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan, and the prodynorphin-derived peptides dynorphin A, dynorphin B, and α- and β-neoendorphin. We used these to select for mutagenesis-validated homology models and docked almost 4 million small molecules. From this docking, we predicted ZINC-3573-a potent MRGPRX2-selective agonist, showing little activity against 315 other GPCRs and 97 representative kinases-along with an essentially inactive enantiomer. ZINC-3573 activates endogenous MRGPRX2 in a human mast cell line, inducing degranulation and calcium release. MRGPRX2 is a unique atypical opioid-like receptor important for modulating mast cell degranulation, which can now be specifically modulated with ZINC-3573.
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“Although 52 non-olfactory GPCRs are categorized as Tdark, the availability of new screening platforms to discover chemical matter for these GPCRs has begun the process of illumination64,67,68.”
From Unexplored therapeutic opportunities in the human genome (2018) · cites this paper as [68]
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Unexplored therapeutic opportunities in the human genome
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Self-citationHouse dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation
Serhan, N., Basso, L., Sibilano, R., Petitfils, C., Meixiong, J., Bonnart, C., Reber, L. L., Marichal, T., Starkl, P. M., Cénac, N., et al. (2019) · Nature Immunology · doi:10.1038/s41590-019-0493-z · Cited by 353
Metadata
- Authors
- Lansu, K., Karpiak, J., Liu, J., Huang, X.-P., McCorvy, J. D., Kroeze, W. K., Che, T., Nagase, H., Carroll, F. I., Jin, J., Shoichet, B. K., & Roth, B. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- University of California, San Francisco (US)
- Icahn School of Medicine at Mount Sinai (US)
- University of Tsukuba (JP)
- RTI International (US)
- Corresponding author
- Roth, Bryan L
- ORCID
- Venue
- Nature Chemical Biology
- Published
- 2017-03-13
- Volume
- 13
- Issue
- 5
- Pages
- 529-536
- ISSN
- 1552-4450 (ISSN-L)
- 1552-4469
- PMC
- PMC5391270
- OpenAlex
- W2595605857
- Cited by
- 293
- References
- 62
- Citations by year
- 2026: 14 · 2025: 36 · 2024: 18 · 2023: 28 · 2022: 30 · 2021: 56 · 2020: 36 · 2019: 35 · 2018: 27 · 2017: 13
- FWCI
- 23.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Chemical Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Mental Health (U19MH082441, U01MH104974)
- National Institute on Drug Abuse (P01DA035764)
- National Institute of General Medical Sciences (T32GM007040)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK116195)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Immunology and Microbiology › Immunology › Mast cells and histamine
- Keywords
- MRGPRX2, G protein-coupled receptors, opioid receptors, chemical probes, dynorphin, mast cell degranulation, calcium release, morphine, sinomenine, dextromethorphan, homology model, molecular docking, pruritus, pain modulation
- MeSH terms
- Calcium, Cell Line, Computer Simulation, Dose-Response Relationship, Drug, Drug Evaluation, Preclinical, Humans, Ligands, Mast Cells, Nerve Tissue Proteins, Pyrazoles, Pyrimidines, Structure-Activity Relationship, Drug Design, Molecular Probes, Molecular Structure, Cell Degranulation, Receptors, Neuropeptide, Receptors, G-Protein-Coupled, Molecular Docking Simulation
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