1. Use of Structure-Based Drug Design Approaches to Obtain Novel Anthranilic Acid Acyl Carrier Protein Synthase Inhibitors
- Author
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Joseph-McCarthy, D., Parris, K., Huang, A., Failli, A., Quagliato, D., Dushin, E. G., Novikova, E., Severina, E., Tuckman, M., Petersen, P. J., Dean, C., Fritz, C. C., Meshulam, T., DeCenzo, M., Dick, L., McFadyen, I. J., Somers, W. S., Lovering, F., and Gilbert, A. M.
- Abstract
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.
- Published
- 2005