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

Research output: Contribution to journalJournal articleResearchpeer-review

Anders Bach, Nicolai Stuhr-Hansen, Thor S Thorsen, Nicolai Bork, Irina S Moreira, Karla Frydenvang, Shahrokh Padrah, S Brøgger Christensen, Kenneth L Madsen, Harel Weinstein, Ulrik Gether, Kristian Strømgaard

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 languageEnglish
JournalOrganic & Biomolecular Chemistry
Volume8
Issue number19
Pages (from-to)4281-4288
Number of pages8
ISSN1477-0520
DOIs
Publication statusPublished - 2010

ID: 21593356