Crystallographic study of inhibitors of tRNA-guanine transglycosylase suggests a new structure-based pharmacophore for virtual screening

J Mol Biol. 2004 Apr 16;338(1):55-75. doi: 10.1016/j.jmb.2004.02.019.

Abstract

The enzyme tRNA-guanine transglycosylase (TGT) is involved in the pathogenicity of Shigellae. As the crystal structure of this protein is known, it is a putative target for the structure-based design of inhibitors. Here we report a crystallographic study of several new ligands exhibiting a 2,6-diamino-3H-quinazolin-4-one scaffold, which has been shown recently to be a promising template for TGT-inhibitors. Crystal structure analysis of these complexes has revealed an unexpected movement of the side-chain of Asp102. A detailed analysis of the water network disrupted by this rotation has lead to the derivation of a new composite pharmacophore. A virtual screening has been performed based on this pharmacophore hypothesis and several new inhibitors of micromolar binding affinity with new skeletons have been discovered.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aspartic Acid / metabolism
  • Binding Sites
  • Combinatorial Chemistry Techniques
  • Crystallography, X-Ray
  • Databases, Factual
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Molecular Structure
  • Pentosyltransferases / chemistry*
  • Pentosyltransferases / metabolism
  • Quinazolines / chemical synthesis*
  • Quinazolines / chemistry*
  • Structure-Activity Relationship
  • Zymomonas / chemistry
  • Zymomonas / enzymology*

Substances

  • Enzyme Inhibitors
  • Ligands
  • Quinazolines
  • Aspartic Acid
  • Pentosyltransferases
  • queuine tRNA-ribosyltransferase