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

Authors

Nguyen Hai Nam, University of Rhode Island
Guofeng Ye, University of Rhode Island
Gongqin Sun, University of Rhode Island
Keykavous Parang, University of Rhode Island

Document Type

Article

Date of Original Version

6-3-2004

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.

Publication Title, e.g., Journal

Journal of Medicinal Chemistry

Volume

47

Issue

12

Citation/Publisher Attribution

Nam, Nguyen Hai, Guofeng Ye, Gongqin Sun, and Keykavous Parang. "Conformationally constrained peptide analogues of pTyr-Glu-Glu-Ile as inhibitors of the Src SH2 domain binding." Journal of Medicinal Chemistry 47, 12 (2004). doi: 10.1021/jm040008+.