Use of structure-based drug design approaches to obtain novel anthranilic acid acyl carrier protein synthase inhibitors.
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.
Joseph-McCarthy
Diane
D
Wyeth Research, 200 CambridgePark Drive, Cambridge, Massachusetts 01240, USA. djoseph@wyeth.com
Parris
Kevin
K
Huang
Adrian
A
Failli
Amedeo
A
Quagliato
Dominick
D
Dushin
Elizabeth Glasfeld
EG
Novikova
Elena
E
Severina
Elena
E
Tuckman
Margareta
M
Petersen
Peter J
PJ
Dean
Charles
C
Fritz
Christian C
CC
Meshulam
Tova
T
DeCenzo
Maureen
M
Dick
Larry
L
McFadyen
Iain J
IJ
Somers
William S
WS
Lovering
Frank
F
Gilbert
Adam M
AM
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
D000900:Anti-Bacterial Agents; D008024:Ligands; D062367:ortho-Aminobenzoates; D017855:Transferases (Other Substituted Phosphate Groups); C021364:holo-(acyl-carrier-protein) synthase