Use of Structure-Based Drug Design Approaches to Obtain Novel Anthranilic Acid Acyl Carrier Protein Synthase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 48; no. 25; pp. 7960 - 7969
• Main Authors: Joseph-McCarthy, Diane, Parris, Kevin, Huang, Adrian, Failli, Amedeo, Quagliato, Dominick, Dushin, Elizabeth Glasfeld, Novikova, Elena, Severina, Elena, Tuckman, Margareta, Petersen, Peter J, Dean, Charles, Fritz, Christian C, Meshulam, Tova, DeCenzo, Maureen, Dick, Larry, McFadyen, Iain J, Somers, William S, Lovering, Frank, Gilbert, Adam M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 15.12.2005; Amer Chemical Soc
• Subjects: Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibacterial agents; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Chemistry, Medicinal; Chromatography, High Pressure Liquid; Crystallography, X-Ray; Drug Design; Drug Resistance, Bacterial; Gram-Positive Bacteria - drug effects; Life Sciences & Biomedicine; Ligands; Medical sciences; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; ortho-Aminobenzoates - chemical synthesis; ortho-Aminobenzoates - chemistry; ortho-Aminobenzoates - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Quantitative Structure-Activity Relationship; Science & Technology; Stereoisomerism; Transferases (Other Substituted Phosphate Groups) - antagonists & inhibitors; Transferases (Other Substituted Phosphate Groups) - chemistry; ENZYME; BIOSYNTHESIS; ESCHERICHIA-COLI; GENES; Acyltransferases; Molecular structure; Enzyme; Transferases; Enzyme inhibitor; Inhibitor enzyme complex; X ray diffraction; In vitro; Modeling; Structure activity relation; Aminoacid; Chlorine Organic compounds; Molecular model; Benzenic compound; Antibacterial agent; Chemical synthesis; Anthranilic acid; Crystalline structure
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050523n

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.