Structure-Based Design of Novel Chk1 Inhibitors: Insights into Hydrogen Bonding and Protein−Ligand Affinity
| Autor: | Andrew Potter, Lisa M. Fisher, Nicolas Foloppe, Peter Kierstan, Allan E. Surgenor, Rob Howes, and Alan G. S. Robertson |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular Molecular model Protein Conformation Stereochemistry Binding energy Molecular Conformation Crystal structure Crystallography X-Ray Ligands Binding Competitive Adenosine Triphosphate Molecular recognition Drug Discovery Humans Enzyme Inhibitors Protein Kinase Inhibitors Binding Sites Bicyclic molecule Chemistry Hydrogen bond Hydrogen Bonding Combinatorial chemistry Kinetics Pyrimidines Docking (molecular) Drug Design Checkpoint Kinase 1 Molecular Medicine Protein Kinases Protein ligand |
| Zdroj: | Journal of Medicinal Chemistry. 48:4332-4345 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm049022c |
| Popis: | We report the discovery, synthesis, and crystallographic binding mode of novel furanopyrimidine and pyrrolopyrimidine inhibitors of the Chk1 kinase, an oncology target. These inhibitors are synthetically tractable and inhibit Chk1 by competing for its ATP site. A chronological account allows an objective comparison of modeled compound docking modes to the subsequently obtained crystal structures. The comparison provides insights regarding the interpretation of modeling results, in relationship to the multiple reasonable docking modes which may be obtained in a kinase-ATP site. The crystal structures were used to guide medicinal chemistry efforts. This led to a thorough characterization of a pair of ligand-protein complexes which differ by a single hydrogen bond. An analysis indicates that this hydrogen bond is expected to contribute a fraction of the 10-fold change in binding affinity, adding a valuable observation to the debate about the energetic role of hydrogen bonding in molecular recognition. |
| Databáze: | OpenAIRE |
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