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

• Published in: Bioorganic & medicinal chemistry letters 2002-05, Vol.12 (10), p.1365-1369
• Main Authors: Hobbs, Christopher J, Bit, Rino A, Cansfield, Andrew D, Harris, Bill, Hill, Christopher H, Hilyard, Katherine L, Kilford, Ian R, Kitas, Eric, Kroehn, Antonin, Lovell, Peter, Pole, David, Rugman, Paul, Sherborne, Brad S, Smith, Ian E D, Vesey, David R, Walmsley, D Lee, Whittaker, David, Williams, Glyn, Wilson, Fiona, Banner, David, Surgenor, Allan, Borkakoti, Neera
• Format: Article
• Language: English
• Subjects: 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; src Homology Domains; Structure-Activity Relationship
• ISSN: 0960-894X
• DOI: 10.1016/S0960-894X(02)00167-1

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.