Development of a screening assay to measure the loss of antibacterial activity in the presence of proteins: its use in optimizing compound structure
| Autor: | Zhuoliang Chen, Ronald Eugene White, Siddhartha Roychoudhury, Wei-Ping Lu, Thomas P. Demuth, Jessica L. Brill |
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| Rok vydání: | 2003 |
| Předmět: |
0301 basic medicine
Staphylococcus aureus Drug Evaluation Preclinical Plasma protein binding Microbial Sensitivity Tests medicine.disease_cause 01 natural sciences Biochemistry Analytical Chemistry 03 medical and health sciences chemistry.chemical_compound Structure-Activity Relationship medicine Potency Bovine serum albumin chemistry.chemical_classification Chromatography biology Dose-Response Relationship Drug Albumin Fatty acid Proteins Serum Albumin Bovine 0104 chemical sciences Anti-Bacterial Agents 010404 medicinal & biomolecular chemistry Oleic acid 030104 developmental biology chemistry biology.protein Linear Models Molecular Medicine Antibacterial activity Staphylococcus Biotechnology |
| Zdroj: | Journal of biomolecular screening. 8(5) |
| ISSN: | 1087-0571 |
| Popis: | An assay quantifying the loss of antibacterial potency of compounds, originally identified via target-based screening, in the presence of increasing albumin concentration was developed and used as a technique to measure potential association of compounds with proteins unrelated to their molecular target. Minimum inhibitory concentrations (MICs) of test compounds were measured against Staphylococcus aureusstrain ATCC 6538 in the presence of 0-12µM bovine serum albumin (BSA). The linear regression coefficient r 2 for the correlation between MIC and BSAconcentration was ≥ 0.9 for 49 and > 0.5 for 62 out of a total of 69 compounds tested. The slope of these correlations varied widely from < 1 to 99, suggesting that the loss of potency due to a given concentration of BSAcould vary from compound to compound due to wide variation in the apparent stoichiometry for protein-ligand association. Follow-up experiments using additional proteins and a fatty acid, oleic acid, showed that this compound:BSAassociation was not protein specific, but was likely driven by hydrophobicity. The method described in this report can be used to optimize compound design and minimize this undesirable effect. (Journal of Biomolecular Screening2003:555-558) |
| Databáze: | OpenAIRE |
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