Synthetic and Crystallographic Studies of a New Inhibitor Series Targeting Bacillus anthracis Dihydrofolate Reductase
| Autor: | Phillip M. Pelphrey, Adrienne E. Smith, Jennifer M. Beierlein, Dennis L. Wright, Nigel D. Priestley, Amy C. Anderson, Tammy M. Joska, David B. Bolstad, Kathleen M. Frey |
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| Rok vydání: | 2008 |
| Předmět: |
Models
Molecular Molecular Sequence Data Microbial Sensitivity Tests Crystallography X-Ray Ligands Article Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Dihydrofolate reductase medicine Humans Structure–activity relationship Amino Acid Sequence Enzyme Inhibitors Antibacterial agent chemistry.chemical_classification Binding Sites Dose-Response Relationship Drug Molecular Structure biology Stereoisomerism biology.organism_classification Trimethoprim Recombinant Proteins Anti-Bacterial Agents Bacillus anthracis Molecular Weight Tetrahydrofolate Dehydrogenase Enzyme chemistry Biochemistry Drug Design Antifolate biology.protein Molecular Medicine Sequence Alignment Lead compound medicine.drug |
| Zdroj: | Journal of Medicinal Chemistry. 51:7532-7540 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm800776a |
| Popis: | Bacillus anthracis, the causative agent of anthrax, poses a significant biodefense danger. Serious limitations in approved therapeutics and the generation of resistance have produced a compelling need for new therapeutic agents against this organism. Bacillus anthracis is known to be insensitive to the clinically used antifolate, trimethoprim, because of a lack of potency against the dihydrofolate reductase enzyme. Herein, we describe a novel lead series of B. anthracis dihydrofolate reductase inhibitors characterized by an extended trimethoprim-like scaffold. The best lead compound adds only 22 Da to the molecular weight and is 82-fold more potent than trimethoprim. An X-ray crystal structure of this lead compound bound to B. anthracis dihydrofolate reductase in the presence of NADPH was determined to 2.25 Å resolution. The structure reveals several features that can be exploited for further development of this lead series. |
| Databáze: | OpenAIRE |
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