Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity
| Autor: | Mark Stidham, Thanh Lam, Bryan P. Kwan, Mark L. Cunningham, Zhiyong Chen, Felice C. Lightstone, Junhu Zhang, Karen J. Shaw, Leslie W. Tari, Toan B. Nguyen, Christopher J. Creighton, John T. Finn, Xiaoming Li, Michael Trzoss, Daniel C. Bensen, Sergio E. Wong, Jay C. Nix |
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| Rok vydání: | 2012 |
| Předmět: |
DNA Topoisomerase IV
Models Molecular Dual targeting Topoisomerase IV Clinical Biochemistry Pharmaceutical Science Biochemistry DNA gyrase Broad spectrum chemistry.chemical_compound Structure-Activity Relationship Drug Discovery Topoisomerase II Inhibitors Pyrroles Molecular Biology chemistry.chemical_classification biology Chemistry Topoisomerase Organic Chemistry biochemical phenomena metabolism and nutrition Anti-Bacterial Agents Enzyme Pyrimidines DNA Gyrase Drug Design biology.protein Molecular Medicine Pharmacophore DNA |
| Zdroj: | Bioorganicmedicinal chemistry letters. 23(5) |
| ISSN: | 1464-3405 |
| Popis: | The bacterial topoisomerases DNA gyrase (GyrB) and topoisomerase IV (ParE) are essential enzymes that control the topological state of DNA during replication. The high degree of conservation in the ATP-binding pockets of these enzymes make them appealing targets for broad-spectrum inhibitor development. A pyrrolopyrimidine scaffold was identified from a pharmacophore-based fragment screen with optimization potential. Structural characterization of inhibitor complexes conducted using selected GyrB/ParE orthologs aided in the identification of important steric, dynamic and compositional differences in the ATP-binding pockets of the targets, enabling the design of highly potent pyrrolopyrimidine inhibitors with broad enzymatic spectrum and dual targeting activity. |
| Databáze: | OpenAIRE |
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