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

被引:30
|
作者
Bach, Anders [2 ]
Stuhr-Hansen, Nicolai [2 ]
Thorsen, Thor S. [1 ]
Bork, Nicolai [3 ]
Moreira, Irina S. [4 ]
Frydenvang, Karla [2 ]
Padrah, Shahrokh [2 ]
Christensen, S. Brogger [2 ]
Madsen, Kenneth L. [1 ]
Weinstein, Harel [4 ]
Gether, Ulrik [1 ]
Stromgaard, Kristian [2 ]
机构
[1] Univ Copenhagen, Panum Inst, Dept Neurosci & Pharmacol, DK-2200 Copenhagen, Denmark
[2] Univ Copenhagen, Dept Med Chem, DK-2100 Copenhagen, Denmark
[3] Tech Univ Denmark, Riso Natl Lab Sustainable Energy, DK-4000 Roskilde, Denmark
[4] Cornell Univ, Weill Med Coll, Dept Physiol & Biophys, New York, NY 10021 USA
基金
美国国家卫生研究院;
关键词
PROTEIN-PROTEIN INTERACTIONS; GLUTAMATE-RECEPTOR SUBUNIT-2; LONG-TERM DEPRESSION; KINASE-C-ALPHA; AMPA RECEPTORS; DRUG DESIGN; HIPPOCAMPAL-NEURONS; MEMBRANE CURVATURE; ANALOG SYNTHESIS; RATIONAL DESIGN;
D O I
10.1039/c0ob00025f
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
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 C alpha-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 PICK! inhibition.
引用
收藏
页码:4281 / 4288
页数:8
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