Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1Electronic supplementary information (ESI) available: General chemistry procedures. Procedures and data for purified compounds. Experimental for biochemical assays and computational docking studies. Analysis of X-ray crystallographic data, NMR data and density functional theory (DFT) calculations for determining the double bond configuration. See DOI: 10.1039/c0ob00025f

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 Cα-kinase 1 (PICK1), a potential drug target against brain ischemia, pain and cocaine addiction. Herein, we explore structure-ac...

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Hauptverfasser: Bach, Anders, Stuhr-Hansen, Nicolai, Thorsen, Thor S, Bork, Nicolai, Moreira, Irina S, Frydenvang, Karla, Padrah, Shahrokh, Christensen, S. Brøgger, Madsen, Kenneth L, Weinstein, Harel, Gether, Ulrik, Strømgaard, Kristian
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Sprache:eng
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Zusammenfassung: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 Cα-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. Structure-activity studies of the first small-molecule inhibitor of the PICK1 PDZ domain leading to improved affinity.
ISSN:1477-0520
1477-0539
DOI:10.1039/c0ob00025f