Ensemble-based ADME-Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE

Chem Biol Drug Des. 2018 Feb;91(2):597-604. doi: 10.1111/cbdd.13124. Epub 2017 Nov 10.


In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ΔCTE, fused benzo[b]thiophenes and β,β'-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate-to-excellent activity (12%-90% inhibition of the target enzyme at 20 μm). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3'-triketones with a Y-topology. Based on the predicted physicochemical and ADME-Tox properties, compound 2b has been identified as a new drug-like, non-mutagen, non-carcinogen, and non-neurotoxic lead candidate.

Keywords: ADME-Tox; benzo[b]thiophenes; cysteine protease; leishmaniasis; triketones.

MeSH terms

  • Binding Sites
  • Catalytic Domain
  • Cell Line
  • Cell Survival / drug effects
  • Cysteine Proteases / chemistry
  • Cysteine Proteases / metabolism*
  • Cysteine Proteinase Inhibitors / chemistry*
  • Cysteine Proteinase Inhibitors / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Leishmania mexicana / drug effects
  • Leishmania mexicana / enzymology*
  • Molecular Docking Simulation
  • Protozoan Proteins / antagonists & inhibitors
  • Protozoan Proteins / metabolism*
  • Structure-Activity Relationship
  • Thiophenes / chemistry*
  • Thiophenes / metabolism
  • Thiophenes / pharmacology


  • Cysteine Proteinase Inhibitors
  • Protozoan Proteins
  • Thiophenes
  • benzothiophene
  • Cysteine Proteases