Structure-based design and discovery of novel inhibitors of protein tyrosine phosphatases
| Autor: | Congxin Liang, John Ramphal, Bahija Jallal, Gerald McMahon, Cho Tang, Ping Huang, James Wei |
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| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Membrane permeability Recombinant Fusion Proteins Clinical Biochemistry Phosphatase Pharmaceutical Science Protein tyrosine phosphatase Biochemistry Structure-Activity Relationship Drug Discovery Structure–activity relationship Humans Sulfones Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Binding Sites biology Chemistry Organic Chemistry Isoenzymes Enzyme Enzyme inhibitor Drug Design biology.protein Molecular Medicine Phosphorylation Signal transduction Protein Tyrosine Phosphatases |
| Zdroj: | Bioorganicmedicinal chemistry. 11(8) |
| ISSN: | 0968-0896 |
| Popis: | Protein tyrosine phosphatases (PTPs) are important in the regulation of signal transduction processes. Certain enzymes of this class are considered as potential therapeutic targets in the treatment of a variety of diseases such as diabetes, inflammation, and cancer. However, many PTP inhibitors identified to date are peptide-based and contain a highly charged phosphate-mimicking component. These compounds usually lack membrane permeability and this limits their utility in the inhibition of intracellular phosphatases. In the present study, we have used structure-based design and modeling techniques to explore catalytic-site directed, reversible inhibitors of PTPs. Employing a non-charged phosphate mimic and non-peptidyl structural components, we have successfully designed and synthesized a novel series of trifluoromethyl sulfonyl and trifluoromethyl sulfonamido compounds as PTP inhibitors. This is the first time that an uncharged phosphate mimic is reported in the literature for general, reversible, and substrate-competitive inhibition of PTPs. It is an important discovery because the finding may provide a paradigm for the development of phosphatase inhibitors that enter cells and modify signal transduction. |
| Databáze: | OpenAIRE |
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