title: Molecular docking screening using agonist-bound GPCR structures: probing the A2A adenosine receptor.
abstract: Crystal structures of G protein-coupled receptors (GPCRs) have recently revealed the molecular basis of ligand binding and activation, which has provided exciting opportunities for structure-based drug design. The A2A adenosine receptor (A2AAR) is a promising therapeutic target for cardiovascular diseases, but progress in this area is limited by the lack of novel agonist scaffolds. We carried out docking screens of 6.7 million commercially available molecules against active-like conformations of the A2AAR to investigate whether these structures could guide the discovery of agonists. Nine out of the 20 predicted agonists were confirmed to be A2AAR ligands, but none of these activated the ARs. The difficulties in discovering AR agonists using structure-based methods originated from limited atomic-level understanding of the activation mechanism and a chemical bias toward antagonists in the screened library. In particular, the composition of the screened library was found to strongly reduce the likelihood of identifying AR agonists, which reflected the high ligand complexity required for receptor activation. Extension of this analysis to other pharmaceutically relevant GPCRs suggested that library screening may not be suitable for targets requiring a complex receptor-ligand interaction network. Our results provide specific directions for the future development of novel A2AAR agonists and general strategies for structure-based drug discovery.
authors.affiliation: †Science for Life Laboratory, Stockholm University, Box 1031, SE-171 21 Solna, Sweden.|‡Swedish e-Science Research Center (SeRC), SE-100 44 Stockholm, Sweden.|§Department of Biochemistry and Biophysics and Center for Biomembrane Research, Stockholm University, SE-106 91 Stockholm, Sweden.
authors.forename: David
authors.initials: D
authors.lastname: Rodríguez
authors.affiliation: ∥Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Zhang-Guo
authors.initials: ZG
authors.lastname: Gao
authors.affiliation: ∥Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Moss
authors.affiliation: ∥Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, United States.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
authors.affiliation: †Science for Life Laboratory, Stockholm University, Box 1031, SE-171 21 Solna, Sweden.|‡Swedish e-Science Research Center (SeRC), SE-100 44 Stockholm, Sweden.|§Department of Biochemistry and Biophysics and Center for Biomembrane Research, Stockholm University, SE-106 91 Stockholm, Sweden.
authors.forename: Jens
authors.initials: J
authors.lastname: Carlsson
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells / Q000187:drug effects; D003412:Cricetulus; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D011446:Prospective Studies; D011487:Protein Conformation; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D043705:Receptor, Adenosine A2A; D043562:Receptors, G-Protein-Coupled