Abstract:

A new class of DNA gyrase inhibitors such as GSK299423 with new mechanism was reported as potent antibacterial activity against multidrug-resistant bacteria. In this work, crystal structure of GSK299423 in complex of DNA gyrase and DNA(PDB code: 2XCS) was utilized for drug design of novel DNA gyrase inhibitors. A pharmacophore model was constructed via the crystal structure of complex. By decoy set validation, the pharmacophore model was demonstrated to possess favorable ability to recognize novel DNA gyrase inhibitors from library. The pharmacophore model and docking method were applied to virtual screen the Screening Compounds library to obtain hit compounds. The hit compound LTH02 was demonstrated to significantly inhibited multidrug-resistant Escherichia coli by antibacterial activity assay, thus the LTH02 as a novel DNA gyrase inhibitor was finally achieved. The pharmacophore model developed could be applied to design more novel DNA gyrase inhibitors and it also provided theoretical basis for further structural modification and synthesis of the inhibitors.

Key words: Novel DNA gyrase inhibitor, Pharmacophore, Virtual screening, Drug-resistant bacteria