Structure based prediction of subtype-selectivity for adenosine receptor antagonists

Neuropharmacology. 2011 Jan;60(1):108-15. doi: 10.1016/j.neuropharm.2010.07.009. Epub 2010 Jul 15.


One of the major hurdles in the development of safe and effective drugs targeting G-protein coupled receptors (GPCRs) is finding ligands that are highly selective for a specific receptor subtype. Structural understanding of subtype-specific binding pocket variations and ligand-receptor interactions may greatly facilitate design of selective ligands. To gain insights into the structural basis of ligand subtype selectivity within the family of adenosine receptors (AR: A(1), A(2A), A(2B), and A(3)) we generated 3D models of all four subtypes using the recently determined crystal structure of the A(A2)AR as a template, and employing the methodology of ligand-guided receptor optimization for refinement. This approach produced 3D conformational models of AR subtypes that effectively explain binding modes and subtype selectivity for a diverse set of known AR antagonists. Analysis of the subtype-specific ligand-receptor interactions allowed identification of the major determinants of ligand selectivity, which may facilitate discovery of more efficient drug candidates.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Binding Sites
  • Ligands
  • Models, Molecular*
  • Protein Binding
  • Protein Conformation
  • Purinergic P1 Receptor Antagonists / pharmacology*
  • Receptors, Purinergic P1 / metabolism*
  • Structure-Activity Relationship


  • Ligands
  • Purinergic P1 Receptor Antagonists
  • Receptors, Purinergic P1