title: Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, University of Copenhagen, Universitetsparken 2, DK-2100, Copenhagen, Denmark.
authors.forename: Anders
authors.initials: A
authors.lastname: Bach
authors.forename: Nicolai
authors.initials: N
authors.lastname: Stuhr-Hansen
authors.forename: Thor S
authors.initials: TS
authors.lastname: Thorsen
authors.forename: Nicolai
authors.initials: N
authors.lastname: Bork
authors.forename: Irina S
authors.initials: IS
authors.lastname: Moreira
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Shahrokh
authors.initials: S
authors.lastname: Padrah
authors.forename: S Brøgger
authors.initials: SB
authors.lastname: Christensen
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Madsen
authors.forename: Harel
authors.initials: H
authors.lastname: Weinstein
authors.forename: Ulrik
authors.initials: U
authors.lastname: Gether
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; C498297:PICk1 protein, human; D054852:Small Molecule Libraries