In silico design of novel probes for the atypical opioid receptor MRGPRX2. Nat Chem Biol 2017 May;13(5):529-536
Date
03/14/2017Pubmed ID
28288109Pubmed Central ID
PMC5391270DOI
10.1038/nchembio.2334Scopus ID
2-s2.0-85015006304 (requires institutional sign-in at Scopus site) 257 CitationsAbstract
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.
Author List
Lansu K, Karpiak J, Liu J, Huang XP, McCorvy JD, Kroeze WK, Che T, Nagase H, Carroll FI, Jin J, Shoichet BK, Roth BLAuthor
John McCorvy PhD Associate Professor in the Cell Biology Neurobiology and Anatomy department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
CalciumCell Degranulation
Cell Line
Computer Simulation
Dose-Response Relationship, Drug
Drug Design
Drug Evaluation, Preclinical
Humans
Ligands
Mast Cells
Molecular Docking Simulation
Molecular Probes
Molecular Structure
Nerve Tissue Proteins
Pyrazoles
Pyrimidines
Receptors, G-Protein-Coupled
Receptors, Neuropeptide
Structure-Activity Relationship
