title: Structure based prediction of subtype-selectivity for adenosine receptor antagonists.
abstract: 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.
authors.affiliation: University of California, San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences, 9500 Gilman Drive, MC-0747, La Jolla, CA 92093, USA.
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Katritch
authors.forename: Irina
authors.initials: I
authors.lastname: Kufareva
authors.forename: Ruben
authors.initials: R
authors.lastname: Abagyan
mesh_terms: D001665:Binding Sites; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D058915:Purinergic P1 Receptor Antagonists / Q000494:pharmacology*; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1