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Binding inhibitors of the bacterial sliding clamp by design
Faculty of Science - Papers (Archive)
  • Gene Wijffels, CSIRO Livestock Industries
  • Wynona M. Johnson, CSIRO Material Science and Engineering
  • Aaron J. Oakley, Australian National University
  • Kathleen Turner, CSIRO Material Science and Engineering
  • V. Chandana Epa, CSIRO Material Science and Engineering
  • Susan J. Briscoe, CSIRO Livestock Industries
  • Mitchell Polley, CSIRO Material Science and Engineering
  • Andris J. Liepa, CSIRO Material Science and Engineering
  • Albert Hofmann, CSIRO Material Science and Engineering
  • Jens Buchardt, University of Queensland
  • Caspar Christensen, University of Queensland
  • Pavel Prosselkov, Australian National University
  • Brian P. Dalrymple, CSIRO Livestock Industries
  • Paul F. Alewood, University of Queensland
  • Philip A. Jennings, CSIRO Livestock Industries
  • Nicholas E Dixon, University of Wollongong
  • David A. Winkler, CSIRO Material Science and Engineering
RIS ID
38055
Publication Date
1-1-2011
Publication Details

Wijffels, G., Johnson, W. M., Oakley, A. J., Turner, K., Epa, V. Chandana., Briscoe, S. J., Polley, M., Liepa, A. J., Hofmann, A., Buchardt, J., Christensen, C., Prosselkov, P., Dalrymple, B. P., Alewood, P. F., Jennings, P. A., Dixon, N. E. & Winkler, D. A. (2011). Binding inhibitors of the bacterial sliding clamp by design. Journal of Medicinal Chemistry, 54 (13), 4831-4838.

Abstract

The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The β2 sliding clamp is an essential component of the replicative machinery, providing a platform for recruitment and function of other replisomal components and ensuring polymerase processivity during DNA replication and repair. A single binding region of the clamp is utilized by its binding partners, which all contain conserved binding motifs. The C-terminal Leu and Phe residues of these motifs are integral to the binding interaction. We acquired three-dimensional structural information on the binding site in β2 by a study of the binding of modified peptides. Development of a three-dimensional pharmacophore based on the C-terminal dipeptide of the motif enabled identification of compounds that on further development inhibited α–β2 interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to β2, as a starting point for further inhibitor design.

Citation Information
Gene Wijffels, Wynona M. Johnson, Aaron J. Oakley, Kathleen Turner, et al.. "Binding inhibitors of the bacterial sliding clamp by design" (2011)
Available at: http://works.bepress.com/nick_dixon/10/