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

  • Author(s): Lansu, Katherine
  • Karpiak, Joel
  • Liu, Jing
  • Huang, Xi-Ping
  • McCorvy, John D
  • Kroeze, Wesley K
  • Che, Tao
  • Nagase, Hiroshi
  • Carroll, Frank I
  • Jin, Jian
  • Shoichet, Brian K
  • Roth, Bryan L
  • et al.
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.

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