Structure-based discovery of beta2-adrenergic receptor ligands

Proc Natl Acad Sci U S A. 2009 Apr 21;106(16):6843-8. doi: 10.1073/pnas.0812657106. Epub 2009 Apr 2.


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 microM, 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic beta-2 Receptor Antagonists
  • Binding Sites
  • Binding, Competitive
  • Cations
  • Databases, Protein
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Inhibitory Concentration 50
  • Kinetics
  • Ligands
  • Models, Molecular
  • Receptors, Adrenergic, beta-2 / chemistry*
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Small Molecule Libraries / pharmacology


  • Adrenergic beta-2 Receptor Antagonists
  • Cations
  • Ligands
  • Receptors, Adrenergic, beta-2
  • Small Molecule Libraries