Ostrov DA, Hernández Prada JA, Corsino PE, Finton KA, Le N, Rowe TC, Discovery of novel DNA gyrase inhibitors by high-throughput virtual screening
Antimicrob Agents Chemother. 2007 Oct;51(10):3688-98, 2007-08-06
Abstract [-]: The bacterial type II topoisomerases DNA gyrase and topoisomerase IV are validated targets for clinically useful quinolone antimicrobial drugs. A significant limitation to widely utilized quinolone inhibitors is the emergence of drug-resistant bacteria due to an altered DNA gyrase. To address this problem, we have used structure-based molecular docking to identify novel drug-like small molecules that target sites distinct from those targeted by quinolone inhibitors. A chemical ligand database containing approximately 140,000 small molecules (molecular weight < 500) was molecularly docked onto two sites of E. coli DNA gyrase targeting: 1) a previously unexplored structural pocket formed at the dimer interface of subunit A, and 2) a small region of the ATP binding pocket on subunit B overlapping the site targeted by coumarin and cyclothialidine drugs. This approach identified several small molecule compounds that inhibited DNA supercoiling activity of purified E. coli DNA gyrase. These compounds are structurally unrelated to previously identified gyrase inhibitors and represent potential scaffolds for optimization of novel antibacterial agents that act on fluoroquinolone-resistant strains.