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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.”
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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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