A Fragment-Based Approach for the Discovery of Isoform-Specific p38α Inhibitors
| Autor: | Jinhua Chen, John L. Stebbins, Ambika Moore, Randy Hoffman, Maurizio Pellecchia, Ziming Zhang, Xiyun Zhang |
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| Rok vydání: | 2007 |
| Předmět: |
Lipopolysaccharides
Gene isoform Plasma protein binding Nuclear Overhauser effect Biology Ligands Biochemistry Cell Line Mitogen-Activated Protein Kinase 14 Structure-Activity Relationship Piperidines Humans Structure–activity relationship Protein Kinase Inhibitors Tumor Necrosis Factor-alpha Kinase General Medicine Isoenzymes Models Chemical Drug Design Nucleic acid Molecular Medicine Pharmacophore Protein Binding Macromolecule |
| Zdroj: | ACS Chemical Biology. 2:329-336 |
| ISSN: | 1554-8937 1554-8929 |
| DOI: | 10.1021/cb700025j |
| Popis: | In this study, we describe a novel approach for lead discovery against protein kinases, pharmacophore by interligand nuclear Overhauser effect (ILOE), in which a pair of ligands that bind to adjacent pockets on the target surface is identified by the detection of protein-mediated ILOEs. We demonstrate that a pharmacophore-based search guided by experimental binding data of weakly interacting fragments can be rapidly and efficiently used to identify (or synthesize) high-affinity, selective ligands. Targeting the inactive state of protein kinases represents a promising approach to achieve selectivity and cellular efficacy. In this respect, when we apply the method for the discovery of potent p38alpha inhibitors, we also demonstrate that the resulting bidentate compounds are highly selective and exhibit a cellular activity that parallels their in vitro binding to the inactive form of the kinase. The method is relatively simple and of general applicability, and as such we anticipate its potential implementation against a variety of macromolecular targets, including not only protein kinases but also those involved in protein-protein interactions or even nucleic acids. |
| Databáze: | OpenAIRE |
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