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Sci Rep. 2015 Mar 5;5:8771. doi: 10.1038/srep08771.

New compound sets identified from high throughput phenotypic screening against three kinetoplastid parasites: an open resource.

Author information

1
Molecular Discovery Research, Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
2
Diseases of the Developing World (DDW), Tres Cantos Medicines Development Campus, GlaxoSmithKline, Tres Cantos, Spain.
3
Department of Microbiology, Division of Parasitology, New York University School of Medicine, New York, NY, USA.
4
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, University of Dundee, Dundee, UK.
5
Instituto de Parasitología y Biomedicina "López-Neyra" Consejo Superior de Investigaciones Cientificas, Granada, Spain.
6
Computational Biology, Quantitative Sciences, GlaxoSmithKline, Collegeville, PA, USA.
7
Computational Biology, Quantitative Sciences, GlaxoSmithKline, Medicines Research Center, Stevenage, Hertfordshire, UK.
8
Chemical Sciences, Molecular Discovery Research, GlaxoSmithKline, Research Triangle Park, NC, USA.

Abstract

Using whole-cell phenotypic assays, the GlaxoSmithKline high-throughput screening (HTS) diversity set of 1.8 million compounds was screened against the three kinetoplastids most relevant to human disease, i.e. Leishmania donovani, Trypanosoma cruzi and Trypanosoma brucei. Secondary confirmatory and orthogonal intracellular anti-parasiticidal assays were conducted, and the potential for non-specific cytotoxicity determined. Hit compounds were chemically clustered and triaged for desirable physicochemical properties. The hypothetical biological target space covered by these diversity sets was investigated through bioinformatics methodologies. Consequently, three anti-kinetoplastid chemical boxes of ~200 compounds each were assembled. Functional analyses of these compounds suggest a wide array of potential modes of action against kinetoplastid kinases, proteases and cytochromes as well as potential host-pathogen targets. This is the first published parallel high throughput screening of a pharma compound collection against kinetoplastids. The compound sets are provided as an open resource for future lead discovery programs, and to address important research questions.

PMID:
25740547
PMCID:
PMC4350103
DOI:
10.1038/srep08771
[Indexed for MEDLINE]
Free PMC Article

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