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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.

SUBMITTER: Rogers JP

PROVIDER: S-EPMC2538531 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Discovery of protein phosphatase 2C inhibitors by virtual screening.

Rogers Jessica P JP Beuscher Albert E AE Flajolet Marc M McAvoy Thomas T Nairn Angus C AC Olson Arthur J AJ Greengard Paul P

Journal of medicinal chemistry 20060301 5

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 an ...[more]

PMID: 16509582

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