Discovery of inhibitors of Schistosoma mansoni HDAC8 by combining homology modeling, virtual screening, and in vitro validation

J Chem Inf Model. 2014 Oct 27;54(10):3005-19. doi: 10.1021/ci5004653. Epub 2014 Oct 2.


Schistosomiasis, caused by S. mansoni, is a tropical disease that affects over 200 million people worldwide. A novel approach for targeting eukaryotic parasites is to tackle their dynamic epigenetic machinery that is necessary for the extensive phenotypic changes during their life cycle. We recently identified S. mansoni histone deacetylase 8 (smHDAC8) as a potential target for antiparasitic therapy. Here we present results from a virtual screening campaign on smHDAC8. Besides hydroxamates, several sulfonamide-thiazole derivatives were identified by a target-based virtual screening using a homology model of smHDAC8. In vitro testing of 75 compounds identified 8 hydroxamates as potent and lead-like inhibitors of the parasitic HDAC8. Solving of the crystal structure of smHDAC8 with two of the virtual screening hits confirmed the predicted binding mode.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding Sites
  • Crystallography, X-Ray
  • Drug Discovery
  • Helminth Proteins / antagonists & inhibitors*
  • Helminth Proteins / chemistry
  • High-Throughput Screening Assays
  • Histone Deacetylase Inhibitors / chemistry*
  • Histone Deacetylases / chemistry*
  • Hydroxamic Acids / chemistry*
  • Ligands
  • Molecular Docking Simulation
  • Protein Binding
  • Schistosoma mansoni / chemistry*
  • Schistosoma mansoni / enzymology
  • Structural Homology, Protein
  • Structure-Activity Relationship
  • Sulfonamides / chemistry*
  • Thiazoles / chemistry*
  • User-Computer Interface


  • Helminth Proteins
  • Histone Deacetylase Inhibitors
  • Hydroxamic Acids
  • Ligands
  • Sulfonamides
  • Thiazoles
  • Histone Deacetylases