Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 16, Pages 6843-6848Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0812657106
Keywords
docking; GPCR; inverse agonists; library bias; ligand design
Categories
Funding
- National Institutes of Health [GM59957, NS28471, F32 GM082028]
- Swiss National Science Foundation Fellowship [PBZHA-118815]
Ask authors/readers for more resources
Aminergic G protein-coupled receptors (GPCRs) have been a major focus of pharmaceutical research for many years. Due partly to the lack of reliable receptor structures, drug discovery efforts have been largely ligand-based. The recently determined X-ray structure of the beta(2)-adrenergic receptor offers an opportunity to investigate the advantages and limitations inherent in a structure-based approach to ligand discovery against this and related GPCR targets. Approximately 1 million commercially available, lead-like molecules were docked against the beta(2)-adrenergic receptor structure. On testing of 25 high-ranking molecules, 6 were active with binding affinities <4 mu M, with the best molecule binding with a K-i of 9 nM(95% confidence interval 7-10 nM). Five of these molecules were inverse agonists. The high hit rate, the high affinity of the most potent molecule, the discovery of unprecedented chemotypes among the new inhibitors, and the apparent bias toward inverse agonists among the docking hits, have implications for structure-based approaches against GPCRs that recognize small organic molecules.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available