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.

Highlights

  • 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

  • This paper reports the application of whole-cell phenotypic assays against L. donovani, T. cruzi and T. brucei to screen the GlaxoSmithKline HTS diversity set of 1.8 million compounds

  • The 1.8 million GlaxoSmithKline HTS screening collection was tested against L. donovani, T. cruzi and T. brucei between October 2012-May 2014 using a primary whole-cell phenotypic screen as described in the Methods

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Summary

Open Resource

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. This paper reports the application of whole-cell phenotypic assays against L. donovani, T. cruzi and T. brucei to screen the GlaxoSmithKline HTS diversity set of 1.8 million compounds. This is the first parallel HTS program which has been disclosed for any pharma compound set against the three kinetoplastids most relevant to human disease. Three kinetoplastid chemical boxes have been assembled and all data are publically available to encourage research and drug discovery efforts in combating these devastating infections

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