Potent dipeptide inhibitors of the pp60c-src SH2 domain

J Med Chem. 1998 May 21;41(11):1894-908. doi: 10.1021/jm970853a.

Abstract

The design, synthesis, and evaluation of dipeptide analogues as ligands for the pp60c-src SH2 domain are described. The critical binding interactions between Ac-Tyr-Glu-N(n-C5H11)2 (2) and the protein are established and form the basis for our structure-based drug design efforts. The effects of changes in both the C-terminal (11-27) and N-terminal (51-69) portions of the dipeptide are explored. Analogues with reduced overall charge (92-95) are also investigated. We demonstrate the feasibility of pairing structurally diverse subunits in a modest dipeptide framework with the goal of increasing the druglike attributes without sacrificing binding affinity.

Publication types

  • Comparative Study

MeSH terms

  • Crystallography, X-Ray
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry
  • Dipeptides / metabolism
  • Dipeptides / pharmacology*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Enzyme-Linked Immunosorbent Assay
  • Humans
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Proto-Oncogene Proteins pp60(c-src) / antagonists & inhibitors*
  • Proto-Oncogene Proteins pp60(c-src) / metabolism
  • Structure-Activity Relationship
  • src Homology Domains*

Substances

  • Dipeptides
  • Enzyme Inhibitors
  • Ligands
  • acetyl-phosphotyrosyl-N,N-dipentylglutamamide
  • Proto-Oncogene Proteins pp60(c-src)