Document Report Card

ID: ALA1141214

Journal: J Med Chem

Title: Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors.

Authors: Joseph-McCarthy D, Parris K, Huang A, Failli A, Quagliato D, Dushin EG, Novikova E, Severina E, Tuckman M, Petersen PJ, Dean C, Fritz CC, Meshulam T, DeCenzo M, Dick L, McFadyen IJ, Somers WS, Lovering F, Gilbert AM.

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.

CiteXplore: 16335920

DOI: 10.1021/jm050523n