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Org Biomol Chem. 2010 Oct 7;8(19):4281-8. doi: 10.1039/c0ob00025f. Epub 2010 Jul 29.

Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1.

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Department of Medicinal Chemistry, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.


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 Calpha-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 PICK1 inhibition.

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