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PDBsum entry 3elc
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References listed in PDB file
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Key reference
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Title
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A structure-Based approach to ligand discovery for 2c-Methyl-D-Erythritol-2,4-Cyclodiphosphate synthase: a target for antimicrobial therapy.
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Authors
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N.L.Ramsden,
L.Buetow,
A.Dawson,
L.A.Kemp,
V.Ulaganathan,
R.Brenk,
G.Klebe,
W.N.Hunter.
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Ref.
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J Med Chem, 2009,
52,
2531-2542.
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PubMed id
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Abstract
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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 Zn(2+)-binding moieties were characterized. One of the putative
Zn(2+)-binding compounds gave the lowest measured K(D) to date (1.92 +/- 0.18
muM). These data provide a framework for the development of IspF inhibitors to
generate lead compounds of therapeutic potential against microbial pathogens.
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