Discovery of Small Molecule WWP2 Ubiquitin Ligase Inhibitors.
We have screened small molecule libraries specifically for inhibitors that target WWP2, an E3 ubiquitin ligase associated with tumour outgrowth and spread. Selected hits demonstrated dose-dependent WWP2 inhibition, low micromolar IC50 values, and inhibition of PTEN substrate-specific ubiquitination. Binding to WWP2 was confirmed by ligand-based NMR spectroscopy. Furthermore, we used ... a combination of STD NMR, the recently developed DEEP-STD NMR approach, and docking calculations, to propose for the first time an NMR-validated 3D molecular model of a WWP2-inhibitor complex. These first generation WWP2 inhibitors provide a molecular framework for informing organic synthetic approaches to improve activity and selectivity.
Mesh Terms:
Binding Sites, Drug Discovery, Enzyme Inhibitors, Humans, Inhibitory Concentration 50, Ligands, Molecular Docking Simulation, Nuclear Magnetic Resonance, Biomolecular, PTEN Phosphohydrolase, Protein Structure, Tertiary, Small Molecule Libraries, Solubility, Ubiquitin-Protein Ligases
Binding Sites, Drug Discovery, Enzyme Inhibitors, Humans, Inhibitory Concentration 50, Ligands, Molecular Docking Simulation, Nuclear Magnetic Resonance, Biomolecular, PTEN Phosphohydrolase, Protein Structure, Tertiary, Small Molecule Libraries, Solubility, Ubiquitin-Protein Ligases
Chemistry
Date: Dec. 03, 2018
PubMed ID: 30207403
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