Binding Inhibitors of the Bacterial Sliding Clamp by Design

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• 作者：Gene Wijffels ; Wynona M. Johnson ; Aaron J. Oakley ; Kathleen Turner ; V. Chandana Epa ; Susan J. Briscoe ; Mitchell Polley ; Andris J. Liepa ; Albert Hofmann ; Jens Buchardt ; Caspar Christensen ; Pavel Prosselkov ; Brian P. Dalrymple ; Paul F. Alewood ; Philip A. Jennings ; Nicholas E. Dixon ; David A. Winkler
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：July 14, 2011
• 年：2011
• 卷：54
• 期：13
• 页码：4831-4838
• 全文大小：916K
• 年卷期：v.54,no.13(July 14, 2011)
• ISSN：1520-4804

文摘

The bacterial replisome is a target for the development of new antibiotics to combat drug resistant strains. The 尾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 尾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 伪鈥撐?sub>2 interaction at low micromolar concentrations. We report the crystal structure of the complex containing one of these inhibitors, a biphenyl oxime, bound to 尾₂, as a starting point for further inhibitor design.