Three-dimensional pharmacophore design and biochemical screening identifies substituted 1,2,4-triazoles as inhibitors of the annexin A2-S100A10 protein interaction

ChemMedChem. 2012 Aug;7(8):1435-46. doi: 10.1002/cmdc.201200107. Epub 2012 May 29.


Protein interactions are increasingly appreciated as targets in small-molecule drug discovery. The interaction between the adapter protein S100A10 and its binding partner annexin A2 is a potentially important drug target. To obtain small-molecule starting points for inhibitors of this interaction, a three-dimensional pharmacophore model was constructed from the X-ray crystal structure of the complex between S100A10 and annexin A2. The pharmacophore model represents the favourable hydrophobic and hydrogen bond interactions between the two partners, as well as spatial and receptor site constraints (excluded volume spheres). Using this pharmacophore model, UNITY flex searches were carried out on a 3D library of 0.7 million commercially available compounds. This resulted in 568 hit compounds. Subsequently, GOLD docking studies were performed on these hits, and a set of 190 compounds were purchased and tested biochemically for inhibition of the protein interaction. Three compounds of similar chemical structure were identified as genuine inhibitors of the binding of annexin A2 to S100A10. The binding modes predicted by GOLD were in good agreement with their UNITY-generated conformations. We synthesised a series of analogues revealing areas critical for binding. Thus computational predictions and biochemical screening can be used successfully to derive novel chemical classes of protein-protein interaction blockers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Annexin A2 / antagonists & inhibitors
  • Annexin A2 / metabolism*
  • Binding Sites
  • Computer Simulation
  • Databases, Chemical
  • Drug Design*
  • Hydrogen Bonding
  • Hydrophobic and Hydrophilic Interactions
  • Protein Interaction Maps
  • Protein Structure, Tertiary
  • S100 Proteins / antagonists & inhibitors
  • S100 Proteins / metabolism*
  • Software
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry*
  • Triazoles / metabolism


  • Annexin A2
  • S100 Proteins
  • S100 calcium binding protein A10
  • Triazoles
  • 1,2,4-triazole