A screening library for peptide activated G-protein coupled receptors. 1. The test set.
One subset of the G-protein coupled receptor (GPCR) superfamily is that which is activated by a peptide carrying an obligatory positively charged residue (GPCR-PA(+)). This subclass is exemplified by receptors for melanocortins, GnRH, galanin, MCH, orexin, and some chemokine receptors variously involved in eating disorders, reproductive disorders, pain, narcolepsy, obesity, and inflammation. Using the methods described in this study, a region of chemical property space enriched in GPCR ligands was identified. This information was used to design and synthesize a "test" library of 2025 single, pure compounds to sample portions of this property space associated with GPCR-PA(+) ligands. The library was evaluated by high-throughput screening against three different receptors, rMCH, hMC4, and hGnRH, and found to be highly enriched in active ligands (4.5-61-fold) compared to a control set of 2024 randomly selected compounds. In addition, the analysis suggested that about 7000 compounds will be necessary to complete the sampling of this GPCR-PA(+) ligand-rich region and to better define its borders.
Lavrador
Karine
K
Chemistry Department, Neurocrine Biosciences, 12790 El Camino Real, San Diego, CA 92130, USA.
Murphy
Brian
B
Saunders
John
J
Struthers
Scott
S
Wang
Xiaochuan
X
Williams
John
J
D000818:Animals; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D008024:Ligands; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism*; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D019151:Peptide Library; D010455:Peptides; D043562:Receptors, G-Protein-Coupled