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 - 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 - https://www.scopus.com/pages/publications/85015006304
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 -