Structure-Based Discovery of A2A Adenosine Receptor Ligands

By J. Carlsson, Lena S. Yoo, Zhang-Guo Gao, John J. Irwin, Brian K. Shoichet, Kenneth A. Jacobson. 2010

216 citations recorded by the source corpus.

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 A2A adenosine receptor, based on complementarity to its recently determined structure. The A2A 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 μM. For the most potent of these new inhibitors, over 50-fold specificity was observed for the A2A versus the related A1 and A3 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.

Subfields: Molecular Biology, Physiology

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Citations in the corpus

Directory of Useful Decoys, Enhanced (DUD-E): Better Ligands and Decoys for Better Benchmarking (2012, background): “Where we had domain knowledge, the most representative structure was preferred, for example a DFG-in structure for 43,44 ).”
Latest developments in molecular docking: 2010–2011 in review (2013, background): “[48] agonist pro ﬁ ling (serotonin 5-HT 1A receptor); [164] design of novel ligands for adenosine A 2A[171,172] and dopamine D 3 .”
Structure-based drug screening for G-protein-coupled receptors. (2012, background): “By contrast, for many soluble proteins, there is little certainty that the “right” molecules exist to be found in our libraries,[31, 32] and their binding sites are often larger, flatter and more exposed to solvent than the orthosteric sites of those GPCRs determined to date.”