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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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Ramsden NL, Buetow L, Dawson A, Kemp LA, Ulaganathan V, Brenk R, Klebe G, Hunter WN
OpenAccess logo J Med Chem 52 2531-42 (2009)
Related entries: 3elc, 3eor, 3ern, 3esj

Cited: 15 times
EuropePMC logo PMID: 19320487

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 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.

Articles - 3fba mentioned but not cited (3)

  1. A structure-based approach to ligand discovery for 2C-methyl-D-erythritol-2,4-cyclodiphosphate synthase: a target for antimicrobial therapy. Ramsden NL, Buetow L, Dawson A, Kemp LA, Ulaganathan V, Brenk R, Klebe G, Hunter WN. J Med Chem 52 2531-2542 (2009)
  2. Elucidating the Origins of High Preferential Crystal Orientation in Quasi-2D Perovskite Solar Cells. Lehner LE, Demchyshyn S, Frank K, Minenkov A, Kubicki DJ, Sun H, Hailegnaw B, Putz C, Mayr F, Cobet M, Hesser G, Schöfberger W, Sariciftci NS, Scharber MC, Nickel B, Kaltenbrunner M. Adv Mater 35 e2208061 (2023)
  3. Two-substrate enzyme engineering using small libraries that combine the substrate preferences from two different variant lineages. Mukhopadhyay A, Karu K, Dalby PA. Sci Rep 14 1287 (2024)


Reviews citing this publication (4)

  1. Molecular recognition in chemical and biological systems. Persch E, Dumele O, Diederich F. Angew Chem Int Ed Engl 54 3290-3327 (2015)
  2. Isoprenoid biosynthesis in bacterial pathogens. Heuston S, Begley M, Gahan CGM, Hill C. Microbiology (Reading) 158 1389-1401 (2012)
  3. Biochemistry of the non-mevalonate isoprenoid pathway. Gräwert T, Groll M, Rohdich F, Bacher A, Eisenreich W. Cell Mol Life Sci 68 3797-3814 (2011)
  4. Isoprenoid precursor biosynthesis offers potential targets for drug discovery against diseases caused by apicomplexan parasites. Hunter WN. Curr Top Med Chem 11 2048-2059 (2011)

Articles citing this publication (8)



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