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

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 - 2010/10/7

Y1 - 2010/10/7

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 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.

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 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.

U2 - 10.1039/c0ob00025f

DO - 10.1039/c0ob00025f

M3 - Journal article

C2 - 20668766

SN - 1477-0520

VL - 8

SP - 4281

EP - 4288

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

IS - 19

ER -