Document Report Card

ID: ALA1138185

Journal: J Med Chem

Title: Discovery of protein phosphatase 2C inhibitors by virtual screening.

Authors: Rogers JP, Beuscher AE, Flajolet M, McAvoy T, Nairn AC, Olson AJ, Greengard P.

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.

CiteXplore: 16509582

DOI: 10.1021/jm051033y