title: Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors.
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.
authors.affiliation: Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 01240, USA. djoseph@wyeth.com
authors.forename: Diane
authors.initials: D
authors.lastname: Joseph-McCarthy
authors.forename: Kevin
authors.initials: K
authors.lastname: Parris
authors.forename: Adrian
authors.initials: A
authors.lastname: Huang
authors.forename: Amedeo
authors.initials: A
authors.lastname: Failli
authors.forename: Dominick
authors.initials: D
authors.lastname: Quagliato
authors.forename: Elizabeth Glasfeld
authors.initials: EG
authors.lastname: Dushin
authors.forename: Elena
authors.initials: E
authors.lastname: Novikova
authors.forename: Elena
authors.initials: E
authors.lastname: Severina
authors.forename: Margareta
authors.initials: M
authors.lastname: Tuckman
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Petersen
authors.forename: Charles
authors.initials: C
authors.lastname: Dean
authors.forename: Christian C
authors.initials: CC
authors.lastname: Fritz
authors.forename: Tova
authors.initials: T
authors.lastname: Meshulam
authors.forename: Maureen
authors.initials: M
authors.lastname: DeCenzo
authors.forename: Larry
authors.initials: L
authors.lastname: Dick
authors.forename: Iain J
authors.initials: IJ
authors.lastname: McFadyen
authors.forename: William S
authors.initials: WS
authors.lastname: Somers
authors.forename: Frank
authors.initials: F
authors.lastname: Lovering
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gilbert
mesh_terms: D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D006094:Gram-Positive Bacteria / Q000187:drug effects; D008024:Ligands; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013237:Stereoisomerism; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D062367:ortho-Aminobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D008024:Ligands; D062367:ortho-Aminobenzoates; D017855:Transferases (Other Substituted Phosphate Groups); C021364:holo-(acyl-carrier-protein) synthase