title: Structure-based discovery of A2A adenosine receptor ligands.
abstract: The recent determination of X-ray structures of pharmacologically relevant GPCRs has made these targets accessible to structure-based ligand discovery. Here we explore whether novel chemotypes may be discovered for the A(2A) adenosine receptor, based on complementarity to its recently determined structure. The A(2A) adenosine receptor signals in the periphery and the CNS, with agonists explored as anti-inflammatory drugs and antagonists explored for neurodegenerative diseases. We used molecular docking to screen a 1.4 million compound database against the X-ray structure computationally and tested 20 high-ranking, previously unknown molecules experimentally. Of these 35% showed substantial activity with affinities between 200 nM and 9 microM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A(2A) versus the related A(1) and A(3) subtypes. These high hit rates and affinities at least partly reflect the bias of commercial libraries toward GPCR-like chemotypes, an issue that we attempt to investigate quantitatively. Despite this bias, many of the most potent new ligands were novel, dissimilar from known ligands, providing new lead structures for modulation of this medically important target.
authors.affiliation: Department of Pharmaceutical Chemistry, University of California, 1700 4th Street, Box 2550, San Francisco, California 94158, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Carlsson
authors.forename: Lena
authors.initials: L
authors.lastname: Yoo
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: John J
authors.initials: JJ
authors.lastname: Irwin
authors.forename: Brian K
authors.initials: BK
authors.lastname: Shoichet
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry*; D003198:Computer Simulation; D055808:Drug Discovery; D006801:Humans; D008024:Ligands; D019636:Neurodegenerative Diseases / Q000188:drug therapy*; D011485:Protein Binding; D043705:Receptor, Adenosine A2A / Q000187:drug effects* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D000893:Anti-Inflammatory Agents; D008024:Ligands; D043705:Receptor, Adenosine A2A; D043562:Receptors, G-Protein-Coupled; D054852:Small Molecule Libraries
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