Molecules | |
Computational Redesign of Bacterial Biotin Carboxylase Inhibitors Using Structure-Based Virtual Screening of Combinatorial Libraries | |
Michal Brylinski1  | |
[1] Division of Biochemistry and Molecular Biology, Louisiana State University, Baton Rouge, LA 70803, USA; E-Mail: | |
关键词:
biotin carboxylase;
acetyl-CoA carboxylase;
biotin carboxylase inhibitors;
amino-oxazole;
combinatorial chemistry;
cheminformatics;
ligand docking;
virtual screening;
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DOI : 10.3390/molecules19044021 | |
来源: mdpi | |
【 摘 要 】
As the spread of antibiotic resistant bacteria steadily increases, there is an urgent need for new antibacterial agents. Because fatty acid synthesis is only used for membrane biogenesis in bacteria, the enzymes in this pathway are attractive targets for antibacterial agent development. Acetyl-CoA carboxylase catalyzes the committed and regulated step in fatty acid synthesis. In bacteria, the enzyme is composed of three distinct protein components: biotin carboxylase, biotin carboxyl carrier protein, and carboxyltransferase. Fragment-based screening revealed that amino-oxazole inhibits biotin carboxylase activity and also exhibits antibacterial activity against Gram-negative organisms. In this report, we redesigned previously identified lead inhibitors to expand the spectrum of bacteria sensitive to the amino-oxazole derivatives by including Gram-positive species. Using 9,411 small organic building blocks, we constructed a diverse combinatorial library of 1.2 × 108 amino-oxazole derivatives. A subset of 9 × 106 of these compounds were subjected to structure-based virtual screening against seven biotin carboxylase isoforms using similarity-based docking by
【 授权许可】
CC BY
© 2014 by the authors; licensee MDPI, Basel, Switzerland.
【 预 览 】
Files | Size | Format | View |
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RO202003190027601ZK.pdf | 4482KB | download |