TY - JOUR
T1 - Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1
AU - Bach, Anders
AU - Stuhr-Hansen, Nicolai
AU - Thorsen, Thor S
AU - Bork, Nicolai
AU - Moreira, Irina S
AU - Frydenvang, Karla
AU - Padrah, Shahrokh
AU - Christensen, S Brøgger
AU - Madsen, Kenneth L
AU - Weinstein, Harel
AU - Gether, Ulrik
AU - Strømgaard, Kristian
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
U2 - 10.1039/c0ob00025f
DO - 10.1039/c0ob00025f
M3 - Journal article
C2 - 20668766
VL - 8
SP - 4281
EP - 4288
JO - Organic & Biomolecular Chemistry
JF - Organic & Biomolecular Chemistry
SN - 1470-4358
IS - 19
ER -