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

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

Author information

1
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands.
2
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands TI Pharma, Leiden, The Netherlands.
3
IOTA Pharmaceuticals, Cambridge, UK.
4
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands University of Dundee, Dundee, UK.
5
Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Belgium.
6
Division of Medicinal Chemistry, Faculty of Sciences, Amsterdam Institute for Molecules, Medicines and Systems (AIMMS), VU University Amsterdam, Amsterdam, The Netherlands r.leurs@vu.nl.

Abstract

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

PMID:
25231971
DOI:
10.1177/1087057114549735
[Indexed for MEDLINE]

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