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Biochem Biophys Res Commun. 2006 Nov 3;349(4):1206-13. Epub 2006 Sep 7.

Biophysical characterization of an indolinone inhibitor in the ATP-binding site of DNA gyrase.

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  • 1Laboratory of Molecular Modeling and NMR Spectroscopy, National Institute of Chemistry, POB660, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.


Fighting bacterial resistance is a challenging task in the field of medicinal chemistry. DNA gyrase represents a validated antibacterial target and has drawn much interest in recent years. By a structure-based approach we have previously discovered compound 1, an indolinone derivative, possessing inhibitory activity against DNA gyrase. In the present paper, a detailed biophysical characterization of this inhibitor is described. Using mass spectrometry, NMR spectroscopy, and fluorescence experiments we have demonstrated that compound 1 binds reversibly to the ATP-binding site of the 24 kDa N-terminal fragment of DNA gyrase B from Escherichia coli (GyrB24) with low micromolar affinity. Based on these data, a plausible molecular model of compound 1 in the active site of GyrB24 was constructed. The predicted binding mode explains the competitive inhibitory mechanism with respect to ATP and forms a useful basis for further development of potent DNA gyrase inhibitors.

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