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

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.

doi:10.1038/nchembio.2334

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

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Author(s): Katherine Lansu ¹ , Joel Karpiak ² , Jing Liu ⁵ , Xi-Ping Huang ¹ ^, ⁶ , John D. McCorvy ¹ , Wesley K. Kroeze ¹ , Tao Che ¹ , Hiroshi Nagase ³ , Frank I. Carroll ⁴ , Jian Jin ⁵ , Brian K. Shoichet ² , Bryan L. Roth ¹ ^, ⁶ ^, ⁷

Publication date (Electronic): 13 March 2017

Journal: Nature chemical biology

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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 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, which represents a potent MRGPRX2-selective agonist, showing little activity against 315 other GPCRs and 97 representative kinases, and 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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Most cited references 59

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Mast cells are primary effectors in allergic reactions, and may have significant roles in diseases by secreting histamine and various inflammatory and immunomodulatory substances 1,2 . While classically they are activated by IgE antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions 1,3 . Roles for these substances in pathology have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, MrgprB2, the orthologue of the human G-protein coupled receptor (GPCR) MrgprX2. Secretagogue-induced histamine release, inflammation, and airway contraction are abolished in MrgprB2 null mutant mice. Further, we show that most classes of FDA-approved peptidergic drugs associated with allergic-type injection-site reactions also activate MrgprB2 and MrgprX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that MrgprB2 and MrgprX2 are targets of many small molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice, and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MrgprX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.

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Author and article information

Journal

Journal ID (nlm-journal-id): 101231976

Journal ID (pubmed-jr-id): 32624

Journal ID (nlm-ta): Nat Chem Biol

Journal ID (iso-abbrev): Nat. Chem. Biol.

Title: Nature chemical biology

ISSN (Print): 1552-4450

ISSN (Electronic): 1552-4469

Publication date Nihms-submitted: 28 December 2016

Publication date (Electronic): 13 March 2017

Publication date (Print): May 2017

Publication date PMC-release: 13 September 2017

Volume: 13

Issue: 5

Pages: 529-536

Affiliations

[1 ]Department of Pharmacology, University of North Carolina, Chapel Hill NC

[2 ]Department of Pharmaceutical Chemistry, University of California, San Francisco, CA

[3 ]University of Tsukuba, International Institute for Integrative Sleep Medicine, Tsukuba, Japan

[4 ]Research Triangle Institute International, Center for Drug Discovery, Research Triangle Park, NC

[5 ]Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY

[6 ]National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina, Chapel Hill NC

[7 ]Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC

Author notes

[†]

These authors contributed equally.

Article

Manuscript ID: NIHMS838886

DOI: 10.1038/nchembio.2334

PMC ID: 5391270

PubMed ID: 28288109

SO-VID: c733f8ed-dbeb-41c9-b81e-22b9f1f3174e

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