The Design and Synthesis of Inhibitors of Imidazoleglycerol Phosphate Dehydratase as Potential Herbicides

Cox, John M.; Hawkes, Timothy R.; Bellini, Peter; Ellis, Russell M.; Barrett, R. C.; Swanborough, Joseph J.; Russell, Sally E.; Walker, Peter A.; Barnes, Nigel J.; Knee, Andrew J.; Lewis, Terence; Davies, Paul R.

doi:10.1002/(sici)1096-9063(199708)50:4<297::aid-ps592>3.0.co;2-2

Cited by 45 publications

(13 citation statements)

References 30 publications

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“…More recently, the histidine biosynthesis in plants has received a lot of attention due to its vital role for plant growth 22. Particularly the sixth enzyme of the pathway, IGPD, has been used as a target for the design of herbicides 23–29…”

Section: Resultsmentioning

confidence: 99%

“…Each manganese ion is coordinated by a glutamate and three histidine residues from two different subunits (Mn 2+ 1 : His47A, His169A, Glu173A, and His74B; Mn 2+ 2 : His170A, His73B, Glu77B, and His145B). The IGPD enzyme has been used as target for the development of herbicides, and several inhibitors of this enzyme are known from these efforts 23–29. The known inhibitors resemble the natural substrate imidazole-glycerol phosphate (IGP).…”

Section: Resultsmentioning

confidence: 99%

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Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays

Henriksen

Liu

Estiú

et al. 2010

Bioorganic & Medicinal Chemistry

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The rapid spread on multi-drug resistant strains of Staphylococcus aureus requires not just novel treatment options, but the development of faster methods for the identification of new hits for drug development. The exponentially increasing speed of computational methods makes a more extensive use in the early stages of drug discovery attractive if sufficient accuracy can be achieved. Computational target identification using systems-level methods suggested the histidine biosynthesis pathway as an attractive target against S. aureus. Potential inhibitors for the pathway were identified through docking, followed by ensemble rescoring that is sufficiently accurate to justify immediate testing of the identified compounds by whole cell assays, avoiding the need for time-consuming and often difficult intermediary enzyme assays. This novel strategy is demonstrated for three key enzymes of the S. aureus histidine biosynthesis pathway, which is predicted to be essential for bacterial biomass productions. Virtual screening of a library of ~10 6 compounds identified 49 potential inhibitors of three enzymes of this pathway. 18 representative compounds were directly tested on three S. aureus-and two E. coli strains in standard disc inhibition assays. 13 compounds are inhibitors of some or all of the S. aureus strains, while 14 compounds weakly inhibit growth in one or both E. coli strains. The high hit rate obtained from a fast virtual screen demonstrates the applicability of this novel strategy to the histidine biosynthesis pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays

Henriksen

Liu

Estiú

et al. 2010

Bioorganic & Medicinal Chemistry

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“…Amino acid biosynthesis pathways, particularly those for aromatic amino acids, ammonia assimilation and branched amino acids, have been confirmed as reasonable herbicidal domains, although the following three key enzymes catalyzing the steps for production of histidine, arginine and methionine may be of use for the molecular design of new herbicides: imidazole‐glycerolphosphate (IGP) dehydratase, ornithine carbamoyltransferase and β‐cystathionase are inhibited by triazole inhibitors (Cox et al . 1997; Ohta et al .…”

Section: Amino Acid Lipid and Cell Wall Biosynthesis And Other Targmentioning

confidence: 99%

Phytotoxic sites of action for molecular design of modern herbicides (Part 2): Amino acid, lipid and cell wall biosynthesis, and other targets for future herbicides

Wakabayashi

Böger

2004

Weed Biology and Management

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A bird's eye review was tried in Part 2 of this series, 'Phytotoxic sites of action for molecular design of modern herbicides', in order to select the best selection of known and some novel plant-specific targets for molecular design of modern herbicides, which affect amino acid, lipid and cell wall biosynthesis. Although amino acid biosynthesis pathways, particularly those for aromatic amino acids, ammonia assimilation and branched amino acids, have been confirmed as reasonable herbicidal target domains, the other targets affecting plant growth more markedly than inhibition of 5-enolpyruvylshikimate-3-phosphate synthase, glutamine synthetase and acetolactate synthase are discussed. In three essential enzymes involved in fatty acid biosynthesis in or in the vicinity of chloroplasts, acetyl-CoA carboxylase (ACCase), elongase(s) for very long chain fatty acids (VLCFA) and linolate monogalactosyldiacylglycerol desaturase, ACCase and elongase are more important targets for new herbicides. Although the effect of cellulose biosynthesis inhibitors is restricted to cell wall formation in growing plant cells only, there is a good chance to design the low-use rate herbicides also in this class of inhibitors. Other possible targets for new herbicides are also discussed.

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“…The antibiotic gostatin also inhibits this enzyme 16. The following three key enzymes that catalyze steps for the production of histidine, arginine and methionine may be of use for new herbicide design: imidazoleglycerol phosphate dehydratase, ornithine carbamoyltransferase and β‐cystathionase are inhibited by the triazole inhibitors,17, 18 phaseolotoxin19 and rhizobitoxin,20 respectively.…”

Section: Ammonia Metabolism and Amino‐acid Biosynthesismentioning

confidence: 99%

Target sites for herbicides: entering the 21st century

Wakabayashi

Böger

2002

Pest Management Science

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At present the use‐rate of modern herbicides is in the range of 100–300 g AI ha−1, with a tendency to decline. The low use‐rate (ca 10 g AI ha−1) of the original sulfonylurea and cyclic imide herbicides prompted agrochemical scientists to look for even more active compounds which led to the successive discoveries of many new herbicidal acetolactate synthase inhibitors and no less than 18 cyclic imides in the class of protoporphyrinogen‐IX oxidase inhibitors in the 1990s. In this paper, mechanisms of action related to function and biosynthesis of chlorophylls, carotenoids, plastoquinone, amino acids, fatty acids and photosynthetic electron transport and other metabolic processes are discussed as plant‐specific herbicidal target domains. © 2002 Society of Chemical Industry

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The Design and Synthesis of Inhibitors of Imidazoleglycerol Phosphate Dehydratase as Potential Herbicides

Cited by 45 publications

References 30 publications

Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays

Identification of novel bacterial histidine biosynthesis inhibitors using docking, ensemble rescoring, and whole-cell assays

Phytotoxic sites of action for molecular design of modern herbicides (Part 2): Amino acid, lipid and cell wall biosynthesis, and other targets for future herbicides

Target sites for herbicides: entering the 21st century

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