Fragment-Based Screening in Tandem with Phenotypic Screening Provides Novel Antiparasitic Hits

Antoni R Blaazer, Kristina M Orrling, Anitha Shanmugham, Chimed Jansen, Louis Maes, Ewald Edink, Geert Jan Sterk, Marco Siderius, Paul England, David Bailey, Iwan J P de Esch, Rob Leurs (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    14 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)131-140
    Number of pages10
    JournalJournal of Biomolecular Screening
    Volume20
    Issue number1
    Early online date17 Sep 2014
    DOIs
    Publication statusPublished - Jan 2015

    Fingerprint

    Antiparasitic Agents
    African Trypanosomiasis
    Screening
    Trypanosoma brucei brucei
    Workflow
    Drug Discovery
    Leishmania infantum
    Leishmaniasis
    Ethers
    Chagas Disease
    Trypanosoma cruzi
    Cyclic Nucleotides
    Phosphoric Diester Hydrolases
    Plasmodium falciparum
    Malaria
    Molecules
    Molecular Weight
    Toxicity
    Lung
    Molecular weight

    Cite this

    Blaazer, A. R., Orrling, K. M., Shanmugham, A., Jansen, C., Maes, L., Edink, E., ... Leurs, R. (2015). Fragment-Based Screening in Tandem with Phenotypic Screening Provides Novel Antiparasitic Hits. Journal of Biomolecular Screening, 20(1), 131-140. https://doi.org/10.1177/1087057114549735
    Blaazer, Antoni R ; Orrling, Kristina M ; Shanmugham, Anitha ; Jansen, Chimed ; Maes, Louis ; Edink, Ewald ; Sterk, Geert Jan ; Siderius, Marco ; England, Paul ; Bailey, David ; de Esch, Iwan J P ; Leurs, Rob. / Fragment-Based Screening in Tandem with Phenotypic Screening Provides Novel Antiparasitic Hits. In: Journal of Biomolecular Screening. 2015 ; Vol. 20, No. 1. pp. 131-140.
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    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.",
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    Blaazer, AR, Orrling, KM, Shanmugham, A, Jansen, C, Maes, L, Edink, E, Sterk, GJ, Siderius, M, England, P, Bailey, D, de Esch, IJP & Leurs, R 2015, 'Fragment-Based Screening in Tandem with Phenotypic Screening Provides Novel Antiparasitic Hits', Journal of Biomolecular Screening, vol. 20, no. 1, pp. 131-140. https://doi.org/10.1177/1087057114549735

    Fragment-Based Screening in Tandem with Phenotypic Screening Provides Novel Antiparasitic Hits. / Blaazer, Antoni R; Orrling, Kristina M; Shanmugham, Anitha; Jansen, Chimed; Maes, Louis; Edink, Ewald; Sterk, Geert Jan; Siderius, Marco; England, Paul; Bailey, David; de Esch, Iwan J P; Leurs, Rob (Lead / Corresponding author).

    In: Journal of Biomolecular Screening, Vol. 20, No. 1, 01.2015, p. 131-140.

    Research output: Contribution to journalArticle

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    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

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