Conformationally constrained peptide analogues of pTyr-Glu-Glu-Ile as inhibitors of the Src SH2 domain binding

Nguyen Hai Nam, Guofeng Ye, Gongqin Sun, Keykavous Parang

Research output: Contribution to journalArticle

Abstract

A series of conformationally constrained peptides were designed and synthesized as the Src SH2 domain ligands based on a tetrapeptide sequence pTyr-Glu-Glu-Ile (pYEEI). In general, the constrained peptides such as compounds 6, 7, and 11 (IC50 = 1.1-1.5 μM) showed higher binding affinities to the Src SH2 domain relative to the corresponding linear peptides 8a, 9a, and 13a, respectively (IC50 > 100 μM), and PYEEI (IC50 = 6.5 μM), as evaluated by a fluorescence polarization assay. Molecular modeling studies revealed that in constrained peptides, the isoleucine side chain penetrates very deeply into the hydrophobic binding pocket (P + 3 site) of the Src SH2 domain. These constrained peptides can serve as novel templates for the design of small and nonpeptidic inhibitors of the Src SH2 domain.

Original languageEnglish (US)
Pages (from-to)3131-3141
Number of pages11
JournalJournal of Medicinal Chemistry
Volume47
Issue number12
DOIs
StatePublished - Jun 3 2004
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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