Small molecule inhibitors of E. coli primase, a novel bacterial target.
Agarwal A,
Louise-May S,
Thanassi JA,
Podos SD,
Cheng J,
Thoma C,
Liu C,
Wiles JA,
Nelson DM,
Phadke AS,
Bradbury BJ,
Deshpande MS,
Pucci MJ.
Achillion Pharmaceuticals, 300 George Street, New Haven, CT 06511, USA.
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.
PMID: 17350255 [PubMed - indexed for MEDLINE]