{"doi":"10.17615/w4az-cw05","title":"In silico design of novel probes for the atypical opioid receptor MRGPRX2","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.","journal":"UNC Libraries","year":2020,"id":143449,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9575,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":166248,"name":"Tao Che","orcid":"0000-0001-6848-7271","position":1,"is_corresponding":false},{"id":611583,"name":"Frank I. Carroll","orcid":null,"position":2,"is_corresponding":false},{"id":444621,"name":"Wesley K. Kroeze","orcid":null,"position":3,"is_corresponding":false},{"id":611050,"name":"Hiroshi Nagase","orcid":"0000-0003-0428-3979","position":4,"is_corresponding":false},{"id":444622,"name":"Joel Karpiak","orcid":null,"position":5,"is_corresponding":false},{"id":225473,"name":"Bryan L. Roth","orcid":"0000-0002-0561-6520","position":6,"is_corresponding":false},{"id":103670,"name":"Xi‐Ping Huang","orcid":"0000-0002-2585-653X","position":7,"is_corresponding":false},{"id":225472,"name":"John D. McCorvy","orcid":"0000-0001-7555-9413","position":8,"is_corresponding":false},{"id":588784,"name":"Katherine Lansu","orcid":"0000-0002-1238-4940","position":9,"is_corresponding":false},{"id":443719,"name":"Jian Jin","orcid":"0000-0001-8586-0429","position":10,"is_corresponding":false},{"id":443206,"name":"Jing Liu","orcid":"0000-0001-5172-4605","position":11,"is_corresponding":false},{"id":106698,"name":"Brian K. Shoichet","orcid":"0000-0002-6098-7367","position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:38.432803Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}