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

Anders Bach; Nicolai Stuhr-Hansen; Thor S Thorsen; Nicolai Bork; Irina S Moreira; Karla Frydenvang; Shahrokh Padrah; S Brøgger Christensen; Kenneth L Madsen; Harel Weinstein; Ulrik Gether; Kristian Strømgaard

doi:10.1039/c0ob00025f

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

Anders Bach, Nicolai Stuhr-Hansen, Thor S Thorsen, Nicolai Bork, Irina S Moreira, Karla Frydenvang, Shahrokh Padrah, S Brøgger Christensen, Kenneth L Madsen, Harel Weinstein, Ulrik Gether, Kristian Strømgaard

27 Citations (Scopus)

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 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.

Original language	English
Journal	Organic & Biomolecular Chemistry
Volume	8
Issue number	19
Pages (from-to)	4281-4288
Number of pages	8
ISSN	1477-0520
DOIs	https://doi.org/10.1039/c0ob00025f
Publication status	Published - 7 Oct 2010

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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 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.",

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year = "2010",

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doi = "10.1039/c0ob00025f",

language = "English",

volume = "8",

pages = "4281--4288",

journal = "Journal of the Chemical Society, Perkin Transactions 1",

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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 - 1470-4358

VL - 8

SP - 4281

EP - 4288

JO - Journal of the Chemical Society, Perkin Transactions 1

JF - Journal of the Chemical Society, Perkin Transactions 1

IS - 19

ER -

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

Abstract

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