Abstract
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.
MeSH terms
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Calcium / metabolism
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Cell Degranulation / drug effects
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Cell Line
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Computer Simulation*
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Dose-Response Relationship, Drug
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Drug Design*
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Drug Evaluation, Preclinical
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Humans
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Ligands
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Mast Cells / drug effects
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Mast Cells / metabolism
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Molecular Docking Simulation
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Molecular Probes / chemical synthesis*
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Molecular Probes / chemistry
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Molecular Probes / pharmacology
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Molecular Structure
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Nerve Tissue Proteins / agonists*
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Nerve Tissue Proteins / genetics
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Nerve Tissue Proteins / metabolism
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacology*
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Receptors, G-Protein-Coupled / agonists*
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Receptors, G-Protein-Coupled / genetics
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Receptors, G-Protein-Coupled / metabolism
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Receptors, Neuropeptide / agonists*
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Receptors, Neuropeptide / genetics
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Receptors, Neuropeptide / metabolism
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Structure-Activity Relationship
Substances
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Ligands
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MRGPRX2 protein, human
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Molecular Probes
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Nerve Tissue Proteins
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Pyrazoles
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Pyrimidines
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Receptors, G-Protein-Coupled
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Receptors, Neuropeptide
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ZINC-72453573
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Calcium
Associated data
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PubChem-Substance/329729401
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PubChem-Substance/329729402
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PubChem-Substance/329729403
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PubChem-Substance/329729404