Structure-based discovery of β₂-adrenergic receptor ligands

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 β₂-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 β₂-adrenergic receptor structure. On testing of 25 high-ranking molecules, 6 were active with binding affinities