TY - JOUR
T1 - In silico design of novel probes for the atypical opioid receptor MRGPRX2
AU - Lansu, Katherine
AU - Karpiak, Joel
AU - Liu, Jing
AU - Huang, Xi Ping
AU - McCorvy, John D.
AU - Kroeze, Wesley K.
AU - Che, Tao
AU - Nagase, Hiroshi
AU - Carroll, Frank I.
AU - Jin, Jian
AU - Shoichet, Brian K.
AU - Roth, Bryan L.
N1 - Funding Information:
Support was given by National Institutes of Health (NIH) grants U01104974 (B.L.R., B.K.S. and W.K.K.), the NIH Department of Pharmacology Training Grant (K.L.), a Genentech Foundation Pre-doctoral Fellowship (J.K.), and a PhRMA Foundation Predoctoral Fellowship (K.L.). We thank the National Institute on Drug Abuse Drug Supply Program for supplying the morphine and codeine analogs and the glucuronidated or acetylated metabolites used in this study.
Publisher Copyright:
© The Author(s) 2017.
PY - 2017/5/1
Y1 - 2017/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85015006304&partnerID=8YFLogxK
U2 - 10.1038/nchembio.2334
DO - 10.1038/nchembio.2334
M3 - Article
C2 - 28288109
AN - SCOPUS:85015006304
SN - 1552-4450
VL - 13
SP - 529
EP - 536
JO - Nature Chemical Biology
JF - Nature Chemical Biology
IS - 5
ER -