Small molecule inhibitors of E. coli primase, a novel bacterial target.
Bacterial primase is essential for DNA replication in Gram-positive and Gram-negative bacteria. It is also structurally distinct from eukaryotic primases, and therefore an attractive, but under-explored, target for therapeutic intervention. We applied virtual screening to discover primase inhibitors, and subsequently several commercially available analogs of these initial hits showed potent primase inhibition and in vitro antibacterial activity. This work provides a 3D pharmacophore for primase ligands, SAR trends, and leads that can be further optimized.
Agarwal
Atul
A
Achillion Pharmaceuticals, 300 George Street, New Haven, CT 06511, USA.
Louise-May
Shirley
S
Thanassi
Jane A
JA
Podos
Steven D
SD
Cheng
Jijun
J
Thoma
Christy
C
Liu
Cuixian
C
Wiles
Jason A
JA
Nelson
David M
DM
Phadke
Avinash S
AS
Bradbury
Barton J
BJ
Deshpande
Milind S
MS
Pucci
Michael J
MJ
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D019915:DNA Primase / Q000037:antagonists & inhibitors* / Q000502:physiology; D004261:DNA Replication / Q000187:drug effects; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology*; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D015394:Molecular Structure; D008970:Molecular Weight
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D019915:DNA Primase