Structure-based design of peptidomimetic antagonists of p56(lck) SH2 domain

Bioorg Med Chem Lett. 2002 May 20;12(10):1365-9. doi: 10.1016/s0960-894x(02)00167-1.

Abstract

Starting from the tetrapeptide Ac-pYEEI-NHMe and using a structure-based approach, we have designed and synthesised a peptidomimetic ligand for p56(lck) SH2 domain containing a conformationally restricted replacement for the two glutamate residues. We have explored replacments for the isoleucine residue in the pY+3 pocket and thus identified 1-(R)-amino-3-(S)-indaneacetic acid as the most potent replacement. We also report the X-ray crystal structures of two of the antagonists.

MeSH terms

  • Animals
  • Cricetinae
  • Crystallography, X-Ray
  • Drug Design
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Glutamic Acid
  • Ligands
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / antagonists & inhibitors*
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / chemistry
  • Models, Molecular
  • Molecular Conformation
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / pharmacology
  • Structure-Activity Relationship
  • src Homology Domains*

Substances

  • Enzyme Inhibitors
  • Ligands
  • Oligopeptides
  • Glutamic Acid
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)