Discovery of novel DNA gyrase inhibitors by high-throughput virtual screening.
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 Escherichia coli DNA gyrase targeting (i) a previously unexplored structural pocket formed at the dimer interface of subunit A and (ii) 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 the DNA supercoiling activity of purified E. coli DNA gyrase. These compounds are structurally unrelated to previously identified gyrase inhibitors and represent potential scaffolds for the optimization of novel antibacterial agents that act on fluoroquinolone-resistant strains.
Department of Pathology, Immunology and Laboratory Medicine, University of Florida, College of Medicine, Gainesville, FL 32610, USA. ostroda@pathology.ufl.edu
David A
DA
Ostrov
José A
JA
Hernández Prada
Patrick E
PE
Corsino
Kathryn A
KA
Finton
Nhan
N
Le
Thomas C
TC
Rowe
D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D003198:Computer Simulation; D003460:Crystallization; D027081:DNA Gyrase / Q000737:chemistry; D004265:DNA Helicases / Q000737:chemistry; D004278:DNA, Superhelical / Q000187:drug effects; D030541:Databases, Genetic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial / Q000187:drug effects / Q000235:genetics; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D007202:Indicators and Reagents; D008968:Molecular Conformation; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D059005:Topoisomerase II Inhibitors; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D027081:DNA Gyrase