Exploring the binding sites of glycogen synthase kinase 3. Identification and characterization of allosteric modulation cavities

J Med Chem. 2011 Dec 22;54(24):8461-70. doi: 10.1021/jm200996g. Epub 2011 Nov 16.


Glycogen synthase kinase 3 (GSK-3) is an important drug target for human severe unmet diseases. Discovery and/or design of allosteric kinase modulators are gaining importance in this field not only for the increased selectivity of this kind of compounds but also for the subtle modulation of the target. This last point is of utmost importance for the GSK-3 inhibition as a therapeutic approach. GSK-3 activity is completely necessary for life, and only the aberrant overactivity found in the pathologies should be inhibited with its inhibitors treatment. We performed here a search for the druggable sites on the enzyme using the fpocket algorithm with the aim to provide allosteric potential binding sites on it and new clues for further drug discoveries. Moreover, our results allowed us to determine the binding sites of different GSK-3 ATP noncompetitive inhibitors, such as manzamine A and the new small molecule VP 0.7, providing evidence for potential allosteric inhibition of GSK-3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Site
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors
  • Glycogen Synthase Kinase 3 / chemistry*
  • Humans
  • Hydrazines / chemical synthesis
  • Hydrazines / chemistry
  • Ligands
  • Models, Molecular*
  • Protein Conformation
  • Quinolones / chemical synthesis
  • Quinolones / chemistry
  • Small Molecule Libraries


  • Hydrazines
  • Ligands
  • Quinolones
  • Small Molecule Libraries
  • small molecule VP 0.7
  • Glycogen Synthase Kinase 3