Binding inhibitors of the bacterial sliding clamp by design

J Med Chem. 2011 Jul 14;54(13):4831-8. doi: 10.1021/jm2004333. Epub 2011 Jun 7.

Abstract

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Binding Sites
  • Crystallography, X-Ray
  • DNA Polymerase III / antagonists & inhibitors*
  • DNA Polymerase III / chemistry
  • Drug Design
  • Hydrophobic and Hydrophilic Interactions
  • Ligands
  • Models, Molecular
  • Molecular Mimicry
  • Oligopeptides / chemical synthesis
  • Oligopeptides / chemistry*
  • Protein Binding
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Surface Plasmon Resonance

Substances

  • Ligands
  • Oligopeptides
  • beta subunit, DNA polymerase III
  • DNA Polymerase III

Associated data

  • PDB/3QSB