Ligand-, structure- and pharmacophore-based molecular fingerprints: a case study on adenosine A(1), A (2A), A (2B), and A (3) receptor antagonists

J Comput Aided Mol Des. 2012 Nov;26(11):1247-66. doi: 10.1007/s10822-012-9612-8. Epub 2012 Oct 12.


FLAP fingerprints are applied in the ligand-, structure- and pharmacophore-based mode in a case study on antagonists of all four adenosine receptor (AR) subtypes. Structurally diverse antagonist collections with respect to the different ARs were constructed by including binding data to human species only. FLAP models well discriminate "active" (=highly potent) from "inactive" (=weakly potent) AR antagonists, as indicated by enrichment curves, numbers of false positives, and AUC values. For all FLAP modes, model predictivity slightly decreases as follows: A(2B)R > A(2A)R > A(3)R > A(1)R antagonists. General performance of FLAP modes in this study is: ligand- > structure- > pharmacophore- based mode. We also compared the FLAP performance with other common ligand- and structure-based fingerprints. Concerning the ligand-based mode, FLAP model performance is superior to ECFP4 and ROCS for all AR subtypes. Although focusing on the early first part of the A(2A), A(2B) and A(3) enrichment curves, ECFP4 and ROCS still retain a satisfactory retrieval of actives. FLAP is also superior when comparing the structure-based mode with PLANTS and GOLD. In this study we applied for the first time the novel FLAPPharm tool for pharmacophore generation. Pharmacophore hypotheses, generated with this tool, convincingly match with formerly published data. Finally, we could demonstrate the capability of FLAP models to uncover selectivity aspects although single AR subtype models were not trained for this purpose.

MeSH terms

  • Adenosine A1 Receptor Antagonists / chemistry*
  • Adenosine A1 Receptor Antagonists / pharmacology
  • Adenosine A2 Receptor Antagonists / chemistry*
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Adenosine A3 Receptor Antagonists / chemistry*
  • Adenosine A3 Receptor Antagonists / pharmacology
  • Humans
  • Ligands
  • Models, Molecular*
  • Molecular Dynamics Simulation
  • Protein Conformation
  • Receptors, Purinergic P1 / chemistry*
  • Structure-Activity Relationship


  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Antagonists
  • Adenosine A3 Receptor Antagonists
  • Ligands
  • Receptors, Purinergic P1