Anti-endotoxin agents. 3. Rapid identification of high-affinity lipopolysaccharide-binding compounds in a substituted polyamine library
| Autor: | Mark R. Burns, Stewart J. Wood, Kelly A. Miller, Sunil A. David, Gerald H. Lushington |
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| Rok vydání: | 2006 |
| Předmět: |
Lipopolysaccharides
Models Molecular Lipopolysaccharide High-throughput screening Drug Evaluation Preclinical Spermine Biology Crystallography X-Ray Lipid A Sepsis chemistry.chemical_compound Structure-Activity Relationship Drug Discovery medicine Polyamines Computer Simulation Molecular Structure Organic Chemistry General Medicine medicine.disease Computer Science Applications Lipopolysaccharide binding chemistry Biochemistry Multivariate Analysis Antitoxins Pharmacophore Polyamine |
| Zdroj: | Combinatorial chemistryhigh throughput screening. 9(1) |
| ISSN: | 1386-2073 |
| Popis: | Lipopolysaccharides (LPS), otherwise termed 'endotoxins', are an integral part of the outer leaflet of the outer-membrane of Gram-negative bacteria. Lipopolysaccharides play a pivotal role in the pathogenesis of 'Septic Shock', a major cause of mortality in the critically ill patient, worldwide. The sequestration of circulatory endotoxin may be a viable therapeutic strategy for the prophylaxis and treatment of Gram-negative sepsis. We have earlier shown that the pharmacophore necessary for small molecules to bind LPS involves two protonatable cationic functions separated by about 15 A, permitting the simultaneous interaction with the negatively charged phosphates on lipid A, the toxically active center of endotoxin. In this report, screening of a multi-thousand membered polyamine library through the combined use of computational and bioassay-guided screens resulted in the discovery of two novel classes of LPS-binding agents. These are represented by the 1) spermine sulfonamides and 2) C-aryl-substituted spermine analogs. We present the selection approach, screening results, computational multivariate analyses and initial structure-activity relationship evaluation herein. |
| Databáze: | OpenAIRE |
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