Projects per year
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 language | English |
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Pages (from-to) | 2531-2542 |
Number of pages | 12 |
Journal | Journal of Medicinal Chemistry |
Volume | 52 |
Issue number | 8 |
DOIs | |
Publication status | Published - 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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Dive into the research topics of 'A Structure-Based Approach to Ligand Discovery for 2C-Methyl-D-erythritol-2,4-cyclodiphosphate Synthase: A Target for Antimicrobial Therapy'. Together they form a unique fingerprint.Projects
- 2 Finished
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Aref#d: 19815. Wellcome Trust Centre for Drug Discovery (Strategic Award)
Fairlamb, A. (Investigator), Ferguson, M. (Investigator) & Frearson, J. (Investigator)
1/01/08 → 31/12/12
Project: Research
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Aref#d: 19401. Structure, specificity and mechanism of biosynthetic enzymes in trypanosomatids and inhibitor discovery of essential microbial functions (Programme Grant)
Hunter, B. (Investigator)
1/11/07 → 31/12/13
Project: Research