1. Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB.
- Author
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Mesleh MF, Cross JB, Zhang J, Kahmann J, Andersen OA, Barker J, Cheng RK, Felicetti B, Wood M, Hadfield AT, Scheich C, Moy TI, Yang Q, Shotwell J, Nguyen K, Lippa B, Dolle R, and Ryan MD
- Subjects
- Adenosine Triphosphatases metabolism, Anti-Bacterial Agents metabolism, Bacterial Proteins metabolism, Binding Sites, Crystallography, X-Ray, DNA Gyrase metabolism, DNA Topoisomerase IV antagonists & inhibitors, DNA Topoisomerase IV metabolism, Drug Design, Escherichia coli metabolism, Ligands, Magnetic Resonance Spectroscopy, Molecular Dynamics Simulation, Protein Binding, Protein Structure, Tertiary, Staphylococcus aureus enzymology, Topoisomerase II Inhibitors metabolism, Anti-Bacterial Agents chemistry, Bacterial Proteins antagonists & inhibitors, DNA Gyrase chemistry, Topoisomerase II Inhibitors chemistry
- Abstract
Inhibitors of the ATPase function of bacterial DNA gyrase, located in the GyrB subunit and its related ParE subunit in topoisomerase IV, have demonstrated antibacterial activity. In this study we describe an NMR fragment-based screening effort targeting Staphylococcus aureus GyrB that identified several attractive and novel starting points with good ligand efficiency. Fragment hits were further characterized using NMR binding studies against full-length S. aureus GyrB and Escherichia coli ParE. X-ray co-crystal structures of select fragment hits confirmed binding and suggested a path for medicinal chemistry optimization. The identification, characterization, and elaboration of one of these fragment series to a 0.265 μM inhibitor is described herein., (Copyright © 2016 Elsevier Ltd. All rights reserved.)
- Published
- 2016
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