A Structure-Based Approach to Ligand Discovery for 2C-Methyl-D-erythritol-2,4-cyclodiphosphate Synthase: A Target for Antimicrobial Therapy

Nicola L. Ramsden, Lori Buetow, Alice Dawson, Lauris A. Kemp, Venkatsubramanian Ulaganathan, Ruth Brenk, Gerhard Klebe, William N. Hunter

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    15 Citations (Scopus)

    Abstract

    The nonmevalonate route to isoprenoid biosynthesis is essential in Gram-negative bacteria and apicomplexan parasites. The enzymes of this pathway are absent from mammals, contributing to their appeal as chemotherapeutic targets. One enzyme, 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase (IspF), has been validated as a target by genetic approaches in bacteria. Virtual screening against Escherichia coli IspF (EcIspF) was performed by combining a hierarchical filtering methodology with molecular docking. Docked compounds were inspected and 10 selected for experimental validation. A surface plasmon resonance assay was developed and two weak ligands identified. Crystal structures of EcIspF complexes were determined to support rational ligand development. Cytosine analogues and Zn2+-binding moieties were characterized. One of the putative Zn2+-binding compounds gave the lowest measured K-D to date (1.92 +/- 0.18 mu M). These data provide a framework for the development of IspF inhibitors to generate lead compounds of therapeutic potential against microbial pathogens.

    Original languageEnglish
    Pages (from-to)2531-2542
    Number of pages12
    JournalJournal of Medicinal Chemistry
    Volume52
    Issue number8
    DOIs
    Publication statusPublished - 23 Apr 2009

    Keywords

    • NON-MEVALONATE PATHWAY
    • ISOPRENOID PRECURSOR BIOSYNTHESIS
    • ESCHERICHIA-COLI
    • 2,4-CYCLODIPHOSPHATE SYNTHASE
    • ISOPENTENYL DIPHOSPHATE
    • ANTIMALARIAL-DRUGS
    • ESSENTIAL ENZYME
    • INHIBITORS
    • BACTERIA
    • DESIGN

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