Limits of ligand selectivity from docking to models: in silico screening for A(1) adenosine receptor antagonists

PLoS One. 2012;7(11):e49910. doi: 10.1371/journal.pone.0049910. Epub 2012 Nov 21.


G protein-coupled receptors (GPCRs) are attractive targets for pharmaceutical research. With the recent determination of several GPCR X-ray structures, the applicability of structure-based computational methods for ligand identification, such as docking, has increased. Yet, as only about 1% of GPCRs have a known structure, receptor homology modeling remains necessary. In order to investigate the usability of homology models and the inherent selectivity of a particular model in relation to close homologs, we constructed multiple homology models for the A(1) adenosine receptor (A(1)AR) and docked ∼2.2 M lead-like compounds. High-ranking molecules were tested on the A(1)AR as well as the close homologs A(2A)AR and A(3)AR. While the screen yielded numerous potent and novel ligands (hit rate 21% and highest affinity of 400 nM), it delivered few selective compounds. Moreover, most compounds appeared in the top ranks of only one model. These findings have implications for future screens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Computer Simulation
  • Ligands
  • Models, Molecular*
  • Molecular Docking Simulation*
  • Protein Binding
  • Protein Conformation*
  • Purinergic P1 Receptor Antagonists / chemistry*
  • Receptors, G-Protein-Coupled / chemistry
  • Receptors, Purinergic P1 / chemistry*


  • Ligands
  • Purinergic P1 Receptor Antagonists
  • Receptors, G-Protein-Coupled
  • Receptors, Purinergic P1