Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors
| Autor: | Diane Joseph-McCarthy, Amedeo Failli, Kevin D. Parris, Quagliato Dominick A, Charles R. Dean, Tova Meshulam, Elena Severina, Adrian Huang, Elizabeth G. Dushin, Margareta Tuckman, Christian C. Fritz, Peter J. Petersen, Iain Mcfadyen, William S Somers, Maureen Decenzo, Frank Lovering, Elena Novikova, Adam M. Gilbert, Larry Dick |
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| Rok vydání: | 2005 |
| Předmět: |
Models
Molecular animal structures Stereochemistry Coenzyme A Quantitative Structure-Activity Relationship Transferases (Other Substituted Phosphate Groups) Microbial Sensitivity Tests Crystallography X-Ray Gram-Positive Bacteria Ligands Serine chemistry.chemical_compound Residue (chemistry) stomatognathic system Drug Discovery Drug Resistance Bacterial Anthranilic acid ortho-Aminobenzoates Chromatography High Pressure Liquid Antibacterial agent biology Acyl carrier protein synthase Molecular Structure Stereoisomerism humanities Anti-Bacterial Agents Acyl carrier protein chemistry Biochemistry Acyltransferases Drug Design biology.protein bacteria Molecular Medicine lipids (amino acids peptides and proteins) |
| Zdroj: | Journal of medicinal chemistry. 48(25) |
| ISSN: | 0022-2623 |
| Popis: | Acyl carrier protein synthase (AcpS) catalyzes the transfer of the 4'-phosphopantetheinyl group from the coenzyme A to a serine residue in acyl carrier protein (ACP), thereby activating ACP, an important step in cell wall biosynthesis. The structure-based design of novel anthranilic acid inhibitors of AcpS, a potential antibacterial target, is presented. An initial high-throughput screening lead and numerous analogues were modeled into the available AcpS X-ray structure, opportunities for synthetic modification were identified, and an iterative process of synthetic modification, X-ray complex structure determination with AcpS, biological testing, and further modeling ultimately led to potent inhibitors of the enzyme. Four X-ray complex structures of representative anthranilic acid ligands bound to AcpS are described in detail. |
| Databáze: | OpenAIRE |
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