Virtual fragment screening for novel inhibitors of 6-phosphogluconate dehydrogenase

Gian Filippo Ruda, Gordon Campbell, Vincent P. Alibu, Michael P. Barrett, Ruth Brenk, Ian H. Gilbert

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    Abstract

    The enzyme 6-phosphogluconate dehydrogenase is a potential drug target for the parasitic protozoan Trypanosoma brucei, the causative organism of human African trypanosomiasis. This enzyme has a polar active site to accommodate the phosphate, hydroxyl and carboxylate groups of the substrate, 6-phosphogluconate. A virtual fragment screen was undertaken of the enzyme to discover starting points for the development of inhibitors which are likely to have appropriate physicochemical properties for an orally bioavailable compound. A virtual screening library was developed, consisting of compounds with functional groups that could mimic the phosphate group of the substrate, but which have a higher pK(a). Following docking, hits were clustered and appropriate compounds purchased and assayed against the enzyme. Three fragments were identified that had IC50 values in the low micromolar range and good ligand efficiencies. Based on these initial hits, analogues were procured and further active compounds were identified. Some of the fragments identified represent potential starting points for a medicinal chemistry programme to develop potent drug-like inhibitors of the enzyme. (C) 2010 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)5056-5062
    Number of pages7
    JournalBioorganic & Medicinal Chemistry
    Volume18
    Issue number14
    DOIs
    Publication statusPublished - 2010

    Keywords

    • Virtual fragment screening
    • Trypanosoma brucei
    • 6-Phosphogluconate dehydrogenase
    • PARASITE TRYPANOSOMA-BRUCEI
    • AFRICAN TRYPANOSOMIASIS
    • BIOLOGICAL EVALUATION
    • ANGSTROM RESOLUTION
    • MOLECULAR DOCKING
    • MECHANISM
    • ANALOGS
    • SPECIFICITY
    • BINDING
    • DRUGS

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