Discovery of Protein Phosphatase 2c Inhibitors by Virtual Screening.
From: Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.
Journal of medicinal chemistry
- Publish Date: Mar 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 5
- Pages: 1658-67
- Medium: Print
- Language: English
- Citation (JAMA): Rogers Jessica P, Beuscher Albert E, Flajolet Marc, et al. Discovery of Protein Phosphatase 2c Inhibitors by Virtual Screening.. J. Med. Chem. Mar 2006;49:1658-67
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.
Mesh Headings (Keywords): Binding Sites, Enzyme Inhibitors, Models, Molecular, Phosphoprotein Phosphatases, Phosphorus Radioisotopes, Quantitative Structure-Activity Relationship
Check for Full Text / PubMed Unique Identifier (PMID): 16509582
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