2. Academic Validation
  3. In silico design of novel probes for the atypical opioid receptor MRGPRX2

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

  • Nat Chem Biol. 2017 May;13(5):529-536. doi: 10.1038/nchembio.2334.
Katherine Lansu 1,  Joel Karpiak 2,  Jing Liu 3,  Xi-Ping Huang 1 4,  John D McCorvy 1,  Wesley K Kroeze 1,  Tao Che 1,  Hiroshi Nagase 5,  Frank I Carroll 6,  Jian Jin 3,  Brian K Shoichet 2,  Bryan L Roth 1 4 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.
  • 2 Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
  • 3 Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
  • 4 National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina, Chapel Hill, North Carolina, USA.
  • 5 International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan.
  • 6 Center for Drug Discovery, Research Triangle Institute International, Research Triangle Park, North Carolina, USA.
  • 7 Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
PMID: 28288109 DOI: 10.1038/nchembio.2334
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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