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

Scientific reports (2015-03-06)
Imanol Peña, M Pilar Manzano, Juan Cantizani, Albane Kessler, Julio Alonso-Padilla, Ana I Bardera, Emilio Alvarez, Gonzalo Colmenarejo, Ignacio Cotillo, Irene Roquero, Francisco de Dios-Anton, Vanessa Barroso, Ana Rodriguez, David W Gray, Miguel Navarro, Vinod Kumar, Alexander Sherstnev, David H Drewry, James R Brown, Jose M Fiandor, J Julio Martin
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Resorufin, 95%
Sigma-Aldrich
Phorbol 12-myristate 13-acetate, ≥99% (TLC), film or powder
Sigma-Aldrich
Phorbol 12-myristate 13-acetate, synthetic, ≥98.0% (TLC)
Sigma-Aldrich
5-Methyl-5-allyloxycarbonyl-1,3-dioxan-2-one, 97%