Design and synthesis of non-peptidic inhibitors for the Syk C-terminal SH2 domain based on structure-based in-silico screening

J Med Chem. 2001 Dec 20;44(26):4737-40. doi: 10.1021/jm010313k.

Abstract

Structure-based in-silico screening was carried out for the Syk C-terminal SH2 domain. Fragments that could interact with the pY or pY+1 pockets were selected by our in-silico screening. After tethering two fragments bound to these pockets, we have designed and synthesized new compounds that show favorable interaction with the pY+3 pocket. One such compound, having a cyclohexylmalonic acid moiety identified as a novel potent phosphotyrosyl mimetic, exhibited an affinity comparable to that of the monophosphorylated ligand peptide.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding, Competitive
  • Cyclohexanes / chemical synthesis*
  • Cyclohexanes / chemistry
  • Enzyme Precursors / antagonists & inhibitors*
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Malonates / chemical synthesis*
  • Malonates / chemistry
  • Models, Molecular
  • Molecular Mimicry
  • Phosphotyrosine / chemistry
  • Protein Structure, Tertiary
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Syk Kinase
  • src Homology Domains*

Substances

  • Cyclohexanes
  • Enzyme Precursors
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • Malonates
  • Phosphotyrosine
  • Protein-Tyrosine Kinases
  • Syk Kinase