Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1.
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.
Bach
Anders
A
Department of Medicinal Chemistry, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
Stuhr-Hansen
Nicolai
N
Thorsen
Thor S
TS
Bork
Nicolai
N
Moreira
Irina S
IS
Frydenvang
Karla
K
Padrah
Shahrokh
S
Christensen
S Brøgger
SB
Madsen
Kenneth L
KL
Weinstein
Harel
H
Gether
Ulrik
U
Strømgaard
Kristian
K
D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D054731:PDZ Domains; D011485:Protein Binding; D054852:Small Molecule Libraries / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D002352:Carrier Proteins; D009687:Nuclear Proteins; C498297:PICk1 protein, human; D054852:Small Molecule Libraries