title: Novel approaches for targeting the adenosine A2A receptor.
abstract: BACKGROUND
  The adenosine A2A receptor (A2AR) represents a drug target for a wide spectrum of diseases. Approaches for targeting this membrane-bound protein have been greatly advanced by new stabilization techniques. The resulting X-ray crystal structures and subsequent analyses provide deep insight to the A2AR from both static and dynamic perspectives. Application of this, along with other biophysical methods combined with fragment-based drug design (FBDD), has become a standard approach in targeting A2AR. Complementarities of in silico screening based- and biophysical screening assisted- FBDD are likely to feature in future approaches in identifying novel ligands against this key receptor.
  
  
  METHODS
  This review describes evolution of the above approaches for targeting A2AR and highlights key modulators identified. It includes a review of: adenosine receptor structures, homology modeling, X-ray structural analysis, rational drug design, biophysical methods, FBDD and in silico screening.
  
  
  CONCLUSIONS
  As a drug target, the A2AR is attractive as its function plays a role in a wide spectrum of diseases including oncologic, inflammatory, Parkinson's and cardiovascular diseases. Although traditional approaches such as high-throughput screening and homology model-based virtual screening (VS) have played a role in targeting A2AR, numerous shortcomings have generally restricted their applications to specific ligand families. Using stabilization methods for crystallization, X-ray structures of A2AR have greatly accelerated drug discovery and influenced development of biophysical-in silico hybrid screening methods. Application of these new methods to other ARs and G-protein-coupled receptors is anticipated in the future.
authors.affiliation: Northeastern University, Department of Chemistry and Chemical Biology , 360 Huntington Ave. 101HT Boston, MA 02115 , USA.
authors.forename: Gengyang
authors.initials: G
authors.lastname: Yuan
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Gedeon
authors.forename: Tanner C
authors.initials: TC
authors.lastname: Jankins
authors.forename: Graham B
authors.initials: GB
authors.lastname: Jones
mesh_terms: D058908:Adenosine A2 Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology; D058917:Adenosine A2 Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology; D000495:Allosteric Site; D000818:Animals; D055592:Biophysical Phenomena; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D058990:Molecular Targeted Therapy; D011485:Protein Binding; D011487:Protein Conformation; D043705:Receptor, Adenosine A2A / Q000737:chemistry / Q000378:metabolism
chemical_list: D058908:Adenosine A2 Receptor Agonists; D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D043705:Receptor, Adenosine A2A
keywords: X-ray crystal structures; adenosine A2A receptor; anti-Parkinson’s disease; biophysical methods; fragment-based drug design; homology modeling; inflammatory disease; virtual screening