title: Small molecule inhibitors of E. coli primase, a novel bacterial target.
abstract: 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.
authors.affiliation: Achillion Pharmaceuticals, 300 George Street, New Haven, CT 06511, USA.
authors.forename: Atul
authors.initials: A
authors.lastname: Agarwal
authors.forename: Shirley
authors.initials: S
authors.lastname: Louise-May
authors.forename: Jane A
authors.initials: JA
authors.lastname: Thanassi
authors.forename: Steven D
authors.initials: SD
authors.lastname: Podos
authors.forename: Jijun
authors.initials: J
authors.lastname: Cheng
authors.forename: Christy
authors.initials: C
authors.lastname: Thoma
authors.forename: Cuixian
authors.initials: C
authors.lastname: Liu
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wiles
authors.forename: David M
authors.initials: DM
authors.lastname: Nelson
authors.forename: Avinash S
authors.initials: AS
authors.lastname: Phadke
authors.forename: Barton J
authors.initials: BJ
authors.lastname: Bradbury
authors.forename: Milind S
authors.initials: MS
authors.lastname: Deshpande
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Pucci
mesh_terms: 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
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D019915:DNA Primase