Exploring the Ribose Sub-Pocket of the Substrate-Binding Site in Escherichia coli IspE: Structure-Based Design, Synthesis, and Biological Evaluation of Cytosines and Cytosine Analogues
| Autor: | Schuetz, Andri P., Osawa, Sho, Mathis, Jennifer, Hirsch, Anna K. H., Bernet, Bruno, Illarionov, Boris, Fischer, Markus, Bacher, Adelbert, Diederich, Francois, Schütz, Andri P. |
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| Přispěvatelé: | Stratingh Institute of Chemistry, Chemical Biology 2 |
| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: |
4-DIPHOSPHOCYTIDYL-2C-METHYL-D-ERYTHRITOL KINASE
Stereochemistry ISOPRENOID BIOSYNTHESIS medicine.disease_cause NON-MEVALONATE PATHWAY Ligand design chemistry.chemical_compound Ribose medicine 1-DEOXY-D-XYLULOSE-5-PHOSPHATE REDUCTOISOMERASE CRYSTAL-STRUCTURE Physical and Theoretical Chemistry Binding site MEDICINAL CHEMISTRY Non-mevalonate pathway DEPENDENT PROTEIN-KINASE Escherichia coli Inhibition chemistry.chemical_classification biology Organic Chemistry Active site PLASMODIUM-FALCIPARUM MALARIA Enzymes Enzyme Biochemistry chemistry NONPHOSPHATE INHIBITORS biology.protein Mevalonate pathway Molecular recognition SUBSTITUTED FOSMIDOMYCIN ANALOGS Cytosine |
| Zdroj: | European Journal of Organic Chemistry, 3278-3287. WILEY-V C H VERLAG GMBH ISSUE=17;STARTPAGE=3278;ENDPAGE=3287;TITLE=European Journal of Organic Chemistry |
| Popis: | The enzymes of the non-mevalonate pathway for the isoprenoid biosynthesis are promising targets for the development of selective drugs for the treatment of important infectious diseases. This pathway is used by plants, many eubacteria, and apicomplexan protozoa, including major human pathogens such as Plasmodium falciparum and Mycobacterium tuberculosis, but not by humans who use the mevalonate pathway. In this work, we report on the design, synthesis, and biological evaluation of new ligands for the E. coli enzyme IspE. The focus of the study lies in the analysis of the ribose sub-pocket of the CDP-ME binding site. Therefore, we synthesized cytosine- and 2-aminopyridine-based inhibitors with various substituents targeting this sub-pocket at the enzyme active site. As cytosines display unexpectedly low solubilities in aqueous solution, special efforts were made to increase the water solubility of some compounds while maintaining the good binding affinities measured in earlier studies. In vitro studies showed IC50 values in the low micromolar to submicromolar range against E. coli IspE. |
| Databáze: | OpenAIRE |
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