Discovery of protein phosphatase 2C inhibitors by virtual screening

J Med Chem. 2006 Mar 9;49(5):1658-67. doi: 10.1021/jm051033y.

Abstract

Protein phosphatase 2C (PP2C) is an archetype of the PPM Ser/Thr phosphatases, characterized by dependence on divalent magnesium or manganese cofactors, absence of known regulatory proteins, and resistance to all known Ser/Thr phosphatase inhibitors. We have used virtual ligand screening with the AutoDock method and the National Cancer Institute Diversity Set to identify small-molecule inhibitors of PP2Calpha activity at a protein substrate. These inhibitors are active in the micromolar range and represent the first non-phosphate-based molecules found to inhibit a type 2C phosphatase. The compounds docked to three recurrent binding sites near the PP2Calpha active site and displayed novel Ser/Thr phosphatase selectivity profiles. Common chemical features of these compounds may form the basis for development of a PP2C inhibitor pharmacophore and may facilitate investigation of PP2C control and cellular function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Binding Sites
  • Enzyme Inhibitors / chemistry*
  • Models, Molecular*
  • Phosphoprotein Phosphatases / antagonists & inhibitors*
  • Phosphoprotein Phosphatases / chemistry*
  • Phosphorus Radioisotopes
  • Protein Phosphatase 2C
  • Quantitative Structure-Activity Relationship*

Substances

  • Enzyme Inhibitors
  • Phosphorus Radioisotopes
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C