Isothiazolidinone heterocycles as inhibitors of protein tyrosine phosphatases: Synthesis and structure–activity relationships of a peptide scaffold
| Autor: | Brian Wayland, Andrew P. Combs, Matthew L. Crawley, Amy Takvorian, Yanlong Li, Eddy W. Yue, Lucie Gonneville, Brent Douty, Erin McLaughlin, Min Wei, Zelda Wasserman, Michael J. Bower, Phillip Liu, Richard Wynn, Timothy Burn, Paul J. Ala |
|---|---|
| Rok vydání: | 2006 |
| Předmět: |
Models
Molecular Stereochemistry Clinical Biochemistry Pharmaceutical Science Protein Tyrosine Phosphatase Non-Receptor Type 11 Peptide Protein tyrosine phosphatase Biochemistry Chemical synthesis Structure-Activity Relationship chemistry.chemical_compound Suzuki reaction Drug Discovery Escherichia coli Humans Molecular Biology Protein Tyrosine Phosphatase Non-Receptor Type 1 chemistry.chemical_classification Dipeptide Molecular Structure biology Protein Tyrosine Phosphatase Non-Receptor Type 6 Organic Chemistry Intracellular Signaling Peptides and Proteins Active site Thiazoles Enzyme chemistry Enzyme inhibitor biology.protein Molecular Medicine Protein Tyrosine Phosphatases Peptides |
| Zdroj: | Bioorganic & Medicinal Chemistry. 14:5833-5849 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2006.05.032 |
| Popis: | The structure-based design and discovery of the isothiazolidinone (IZD) heterocycle as a mimic of phosphotyrosine (pTyr) has led to the identification of novel IZD-containing inhibitors of protein tyrosine phosphatase 1B (PTP1B). The structure–activity relationships (SARs) of peptidic IZD-containing inhibitors of PTP1B are described along with a novel synthesis of the aryl-IZD fragments via a Suzuki coupling. The SAR revealed the saturated IZD heterocycle (42) is the most potent heterocyclic pTyr mimetic compared to the unsaturated IZD (25), the thiadiazolidinone (TDZ) (38), and the regioisomeric unsaturated IZD (31). The X-ray crystal structures of 11c and 25 complexed with PTP1B were solved and revealed nearly identical binding interactions in the active site. Ab initio calculations effectively explain the strong binding of the (S)-IZD due to the preorganized binding of the IZD in its low energy conformation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect