Computer-aided identification of Trypanosoma brucei uridine diphosphate galactose 4 '-epimerase inhibitors: toward the development of novel therapies for African sleeping sickness

Jacob D. Durrant, Michael D. Urbaniak, Michael A. J. Ferguson, J. Andrew McCammon

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    40 Citations (Scopus)

    Abstract

    Trypanosoma brucei, the causative agent of human African trypanosomiasis, affects tens of thousands of sub-Saharan Africans. As current therapeutics are inadequate due to toxic side effects, drug resistance, and limited effectiveness, novel therapies are urgently needed. UDP-galactose 4'-epimerase (TbGalE), an enzyme of the Leloir pathway of galactose metabolism, is one promising T. brucei drug target. We here use the relaxed complex scheme, an advanced computer-docking methodology that accounts for full protein flexibility, to identify inhibitors of TbGalE. An initial hit rate of 62% was obtained at 100 mu M, ultimately leading to the identification of 14 low-micromolar inhibitors. Thirteen of these inhibitors belong to a distinct series with a conserved binding motif that may prove useful in future drug design and optimization.

    Original languageEnglish
    Pages (from-to)5025-5032
    Number of pages8
    JournalJournal of Medicinal Chemistry
    Volume53
    Issue number13
    DOIs
    Publication statusPublished - 8 Jul 2010

    Keywords

    • RELAXED COMPLEX SCHEME
    • CELL-FREE MEDIUM
    • MOLECULAR-DYNAMICS
    • DRUG-RESISTANCE
    • BIOMOLECULAR SIMULATION
    • ALLOSTERIC MODULATORS
    • RECEPTOR FLEXIBILITY
    • NATURAL-PRODUCTS
    • DISCOVERY
    • PROTEIN

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