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

Org Biomol Chem. 2010 Oct 7;8(19):4281-8. doi: 10.1039/c0ob00025f. Epub 2010 Jul 29.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / chemistry
  • Carrier Proteins / metabolism*
  • Crystallography, X-Ray
  • Humans
  • Models, Molecular
  • Nuclear Proteins / antagonists & inhibitors*
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / metabolism*
  • PDZ Domains*
  • Protein Binding
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology*
  • Structure-Activity Relationship


  • Carrier Proteins
  • Nuclear Proteins
  • PICk1 protein, human
  • Small Molecule Libraries