Structure-based Design of Selective and Potent Inhibitors of Protein-tyrosine Phosphatase β
| Autor: | Karin Bach Møller, Niels Møller, Lars Fogh Iversen, Frank U. Axe, Anja K. Pedersen, Ole Hvilsted Olsen, Ida Katrine Lund, Michael J. Newman, Yu Ge, Henrik Sune Andersen, Daniel D. Holsworth |
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| Rok vydání: | 2004 |
| Předmět: |
Leptin
Models Molecular Molecular model Protein Conformation medicine.medical_treatment Mutant Phosphatase Phthalimides Protein tyrosine phosphatase Biology Crystallography X-Ray Ligands Biochemistry Structure-Activity Relationship medicine Insulin Cloning Molecular Enzyme Inhibitors Molecular Biology Protein Tyrosine Phosphatase Non-Receptor Type 1 chemistry.chemical_classification Temperature Wild type Hydrogen Bonding Cell Biology Kinetics Enzyme Models Chemical chemistry Drug Design Mutation Protein Tyrosine Phosphatases Signal transduction Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 279:24226-24235 |
| ISSN: | 0021-9258 |
| Popis: | Protein-tyrosine phosphatases (PTPs) are considered important therapeutic targets because of their pivotal role as regulators of signal transduction and thus their implication in several human diseases such as diabetes, cancer, and autoimmunity. In particular, PTP1B has been the focus of many academic and industrial laboratories because it was found to be an important negative regulator of insulin and leptin signaling, and hence a potential therapeutic target in diabetes and obesity. As a result, significant progress has been achieved in the design of highly selective and potent PTP1B inhibitors. In contrast, little attention has been given to other potential drug targets within the PTP family. Guided by x-ray crystallography, molecular modeling, and enzyme kinetic analyses with wild type and mutant PTPs, we describe the development of a general, low molecular weight, non-peptide, non-phosphorus PTP inhibitor into an inhibitor that displays more than 100-fold selectivity for PTPbeta over PTP1B. Of note, our structure-based design principles, which are based on extensive bioinformatics analyses of the PTP family, are general in nature. Therefore, we anticipate that this strategy, here applied to PTPbeta, in principle can be used in the design and development of selective inhibitors of many, if not most PTPs. |
| Databáze: | OpenAIRE |
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