title: Discovery of protein phosphatase 2C inhibitors by virtual screening.
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.
authors.affiliation: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
authors.forename: Jessica P
authors.initials: JP
authors.lastname: Rogers
authors.forename: Albert E
authors.initials: AE
authors.lastname: Beuscher
authors.forename: Marc
authors.initials: M
authors.lastname: Flajolet
authors.forename: Thomas
authors.initials: T
authors.lastname: McAvoy
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Arthur J
authors.initials: AJ
authors.lastname: Olson
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
mesh_terms: D001665:Binding Sites; D004791:Enzyme Inhibitors / Q000737:chemistry*; D008958:Models, Molecular; D010749:Phosphoprotein Phosphatases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010761:Phosphorus Radioisotopes; D000071636:Protein Phosphatase 2C; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D010761:Phosphorus Radioisotopes; D010749:Phosphoprotein Phosphatases; D000071636:Protein Phosphatase 2C