Structure-based discovery of β 2 -adrenergic receptor ligands

Peter Kolb, Daniel M. Rosenbaum, John J. Irwin, Juan José Fung, Brian K. Kobilka, Brian K. Shoichet

Research output: Contribution to journalArticleResearchpeer-review

252 Citations (Scopus)

Abstract

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 β 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 β 2- adrenergic receptor structure. On testing of 25 high-ranking molecules, 6 were active with binding affinities <4 μM, with the best molecule binding with a K, of 9nM (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.

Original languageEnglish
Pages (from-to)6843-6848
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number16
DOIs
Publication statusPublished - 21 Apr 2009
Externally publishedYes

Keywords

  • Docking
  • GPCR
  • Inverse agonists
  • Library bias
  • Ligand design

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