Binding evaluation of fragment-based scaffolds for probing allosteric enzymes

J Med Chem. 2012 Feb 9;55(3):1287-95. doi: 10.1021/jm201439b. Epub 2012 Jan 24.


Fragment-based drug discovery has become a powerful method for the generation of drug leads against therapeutic targets. Beyond the identification of novel and effective starting points for drug design, fragments have emerged as reliable tools for assessing protein druggability and identifying protein hot spots. Here, we have examined fragments resulting from the deconstruction of known inhibitors from the glycogen phosphorylase enzyme, a therapeutic target against type 2 diabetes, with two motivations. First, we have analyzed the fragment binding to the multiple binding sites of the glycogen phosphorylase, and then we have investigated the use of fragments to study allosteric enzymes. The work we report illustrates the power of fragmentlike ligands not only for probing the various binding pockets of proteins, but also for uncovering cooperativity between these various binding sites.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Binding Sites
  • Enzyme Inhibitors / chemistry*
  • Glycogen Phosphorylase / antagonists & inhibitors
  • Glycogen Phosphorylase / chemistry*
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Models, Molecular*
  • Protein Binding
  • Structure-Activity Relationship


  • Enzyme Inhibitors
  • Ligands
  • Glycogen Phosphorylase