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 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.
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Lansu
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Joel
authors.initials: J
authors.lastname: Karpiak
authors.affiliation: Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.|National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Xi-Ping
authors.initials: XP
authors.lastname: Huang
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: McCorvy
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Wesley K
authors.initials: WK
authors.lastname: Kroeze
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Che
authors.affiliation: International Institute for Integrative Sleep Medicine, University of Tsukuba, Tsukuba, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.affiliation: Center for Drug Discovery, Research Triangle Institute International, Research Triangle Park, North Carolina, USA.
authors.forename: Frank I
authors.initials: FI
authors.lastname: Carroll
authors.affiliation: Department of Pharmacological Sciences and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina, USA.|National Institute of Mental Health Psychoactive Drug Screening Program (NIMH PDSP), University of North Carolina, Chapel Hill, North Carolina, USA.|Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
mesh_terms: D002118:Calcium / Q000378:metabolism; D015550:Cell Degranulation / Q000187:drug effects; D002460:Cell Line; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D008407:Mast Cells / Q000187:drug effects / Q000378:metabolism; D062105:Molecular Docking Simulation; D015335:Molecular Probes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D018013:Receptors, Neuropeptide / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; C480039:MRGPRX2 protein, human; D015335:Molecular Probes; D009419:Nerve Tissue Proteins; D011720:Pyrazoles; D011743:Pyrimidines; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; C000617638:ZINC-72453573; D002118:Calcium