Cited by 298Computational Drug Discovery MethodsReceptor Mechanisms and SignalingMast cells and histamine

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

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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·2017·Nature Chemical Biology

DOI 10.1038/nchembio.2334PMC PMC5391270

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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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BindingDB (2020) · UC San Diego · doi:10.7270/q2bg2rjk
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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: Lansu, Katherine
Karpiak, Joel
Liu, Jing
Huang, Xi-Ping
McCorvy, John D
Che, Tao
Carroll, Frank I
Jin, Jian
Shoichet, Brian K
Roth, Bryan L
Venue: Nature Chemical Biology
Publisher: Springer Science and Business Media LLC
Published: 2017-03-13
Volume: 13
Issue: 5
Pages: 529-536
ISSN: 1552-4450 (ISSN-L)
1552-4469
DOI: 10.1038/nchembio.2334
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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