Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 8, Issue 19, Pages 4281-4288Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/c0ob00025f
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Funding
- Lundbeck Foundation
- Drug Research Academy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Denmark
- University of Copenhagen
- National Institutes of Health [P01 DA012408]
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Recently, we described the first small-molecule inhibitor, (E)-ethyl 2-cyano-3-(3,4-dichlorophenyl)acryloylcarbamate (1), of the PDZ domain of protein interacting with C alpha-kinase 1 (PICK1), a potential drug target against brain ischemia, pain and cocaine addiction. Herein, we explore structure-activity relationships of 1 by introducing subtle modifications of the acryloylcarbamate scaffold and variations of the substituents on this scaffold. The configuration around the double bond of 1 and analogues was settled by a combination of X-ray crystallography, NMR and density functional theory calculations. Thereby, docking studies were used to correlate biological affinities with structural considerations for ligand-protein interactions. The most potent analogue obtained in this study showed an improvement in affinity compared to 1 and is currently a lead in further studies of PICK! inhibition.
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