Title

Binding inhibitors of the bacterial sliding clamp by design

RIS ID

38055

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.

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Link to publisher version (DOI)

http://dx.doi.org/10.1021/jm2004333