In silico design of novel probes for the atypical opioid receptor MRGPRX2

Katherine Lansu, Joel Karpiak, Jing Liu, Xi Ping Huang, John D. McCorvy, Wesley K. Kroeze, Tao Che, Hiroshi Nagase, Frank I. Carroll, Jian Jin, Brian K. Shoichet, Bryan L. Roth

Research output: Contribution to journalArticlepeer-review

194 Scopus citations


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.

Original languageEnglish
Pages (from-to)529-536
Number of pages8
JournalNature Chemical Biology
Issue number5
StatePublished - May 1 2017


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