TY - JOUR
T1 - Fragment-Based Screening in Tandem with Phenotypic Screening Provides Novel Antiparasitic Hits
AU - Blaazer, Antoni R
AU - Orrling, Kristina M
AU - Shanmugham, Anitha
AU - Jansen, Chimed
AU - Maes, Louis
AU - Edink, Ewald
AU - Sterk, Geert Jan
AU - Siderius, Marco
AU - England, Paul
AU - Bailey, David
AU - de Esch, Iwan J P
AU - Leurs, Rob
N1 - © 2014 Society for Laboratory Automation and Screening.
PY - 2015/1
Y1 - 2015/1
N2 - 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.
AB - 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.
U2 - 10.1177/1087057114549735
DO - 10.1177/1087057114549735
M3 - Article
C2 - 25231971
SN - 1087-0571
VL - 20
SP - 131
EP - 140
JO - Journal of Biomolecular Screening
JF - Journal of Biomolecular Screening
IS - 1
ER -