Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1
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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 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.
Original language | English |
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Journal | Organic & Biomolecular Chemistry |
Volume | 8 |
Issue number | 19 |
Pages (from-to) | 4281-4288 |
Number of pages | 8 |
ISSN | 1477-0520 |
DOIs | |
Publication status | Published - 2010 |
ID: 21593356