Fragment-based discovery of DNA gyrase inhibitors targeting the ATPase subunit of GyrB

Autor: Michael F. Mesleh, Joseph Shotwell, Terence Moy, Jan Kahmann, Michael W. Wood, Andrea T. Hadfield, Ole A. Andersen, Roland E. Dolle, M. Dominic Ryan, John M. Barker, Brunella Felicetti, Kien T. Nguyen, Christoph Scheich, Jason B. Cross, Qingyi Yang, Jing Zhang, Lippa Blaise S, Robert K. Y. Cheng
Rok vydání: 2015
Předmět:
DNA Topoisomerase IV
Staphylococcus aureus
Magnetic Resonance Spectroscopy
Topoisomerase IV
Protein subunit
Clinical Biochemistry
Pharmaceutical Science
Plasma protein binding
Molecular Dynamics Simulation
medicine.disease_cause
Crystallography
X-Ray
Ligands
01 natural sciences
Biochemistry
DNA gyrase
Bacterial Proteins
Drug Discovery
medicine
Escherichia coli
Topoisomerase II Inhibitors
Binding site
Molecular Biology
Adenosine Triphosphatases
Ligand efficiency
Binding Sites
biology
010405 organic chemistry
Chemistry
Organic Chemistry
biochemical phenomena
metabolism
and nutrition
0104 chemical sciences
Anti-Bacterial Agents
Protein Structure
Tertiary
010404 medicinal & biomolecular chemistry
DNA Gyrase
Drug Design
biology.protein
Molecular Medicine
Topoisomerase-II Inhibitor
Protein Binding
Zdroj: Bioorganicmedicinal chemistry letters. 26(4)
ISSN: 1464-3405
Popis: 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.
Databáze: OpenAIRE
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