Fragment-based screening in tandem with phenotypic screening provides novel antiparasitic hits

J Biomol Screen. 2015 Jan;20(1):131-40. doi: 10.1177/1087057114549735. Epub 2014 Sep 17.


Methods to discover biologically active small molecules include target-based and phenotypic screening approaches. One of the main difficulties in drug discovery is elucidating and exploiting the relationship between drug activity at the protein target and disease modification, a phenotypic endpoint. Fragment-based drug discovery is a target-based approach that typically involves the screening of a relatively small number of fragment-like (molecular weight <300) molecules that efficiently cover chemical space. Here, we report a fragment screening on TbrPDEB1, an essential cyclic nucleotide phosphodiesterase (PDE) from Trypanosoma brucei, and human PDE4D, an off-target, in a workflow in which fragment hits and a series of close analogs are subsequently screened for antiparasitic activity in a phenotypic panel. The phenotypic panel contained T. brucei, Trypanosoma cruzi, Leishmania infantum, and Plasmodium falciparum, the causative agents of human African trypanosomiasis (sleeping sickness), Chagas disease, leishmaniasis, and malaria, respectively, as well as MRC-5 human lung cells. This hybrid screening workflow has resulted in the discovery of various benzhydryl ethers with antiprotozoal activity and low toxicity, representing interesting starting points for further antiparasitic optimization.

Keywords: antiparasitic activity; cell-based screening; fragment-based drug discovery (FBDD); neglected tropical diseases (NTDs); phenotypic drug discovery (PDD); phenotypic screening; phosphodiesterase (PDE) inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3',5'-Cyclic-AMP Phosphodiesterases / antagonists & inhibitors
  • Antiparasitic Agents / chemistry
  • Antiparasitic Agents / pharmacology*
  • Chagas Disease / drug therapy
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Drug Discovery / methods*
  • Drug Evaluation, Preclinical / methods
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Neglected Diseases / drug therapy
  • Parasitic Sensitivity Tests / methods*
  • Protozoan Proteins / antagonists & inhibitors
  • Trypanosoma cruzi / drug effects
  • Trypanosoma cruzi / enzymology


  • Antiparasitic Agents
  • Enzyme Inhibitors
  • Protozoan Proteins
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • PDE4D protein, human
  • PDEB1 protein, Trypanosoma brucei