Binding Inhibitors of the Bacterial Sliding Clamp by Design

作者：Wijffels Gene^*; Johnson Wynona M; Oakley Aaron J; Turner Kathleen; Epa V Chandana; Briscoe Susan J; Polley Mitchell; Liepa Andris J; Hofmann Albert; Buchardt Jens; Christensen Caspar; Prosselkov Pavel; Dalrymple Brian P; Alewood Paul F; Jennings Philip A; Dixon Nicholas E; Winkler David A

来源：Journal of Medicinal Chemistry, 2011, 54(13): 4831-4838.

DOI：10.1021/jm2004333

The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The beta(2) 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 beta(2) 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 alpha-beta(2) interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to beta(2), as a starting point for further inhibitor design.

• 出版日期2011-7-14
• 单位CSIRO