Design and synthesis of conformationally constrained, extended and reverse turn pseudopeptides as Grb2-SH2 domain antagonists

Preorganization in biological systems: Are conformational constraints worth the energy?

“…Compounds that selectively block binding to SH2 domains have thus been pursued for studying mechanisms of signal transduction and for their potential as drug candidates to treat cancer and other diseases. Structural studies of complexes of Src SH2 domains with phosphopeptides related to pTyr-Glu-Glu-Ile (pYEEI) (10) reveal that these antagonists bind to the Src SH2 domain in extended conformations in which two well-defined binding pockets on the SH2 domain accommodate the pTyr residue and the hydrophobic residue (e.g., Ile, etc.) at the pY+3 position.…”

“…Amide bond formation between 19 and 23 and protected Glu-Glu-Ile tripeptides using standard peptide-coupling procedures followed by global deprotection then delivered 12 and 13 [9]. Pseudopeptides 14 and 15 were similarly prepared from 19 and 23 and a Val-Asn-NH 2 dipeptide [10]. …”

Ligand Preorganization May Be Accompanied by Entropic Penalties in Protein–Ligand Interactions

“…flexible analogues of Ac-pTyr-Val-Asn-NH 2 (1). [24] As in our previous studies of Src SH2 binding ligands, the cyclopropane ring in 2 serves as a rigid mimic of the pTyr residue in 1, whereas a benzyl succinyl moiety is a flexible pTyr replacement in the control 3. The thermodynamic parameters (DG, DH, DS) for binding of 2 and 3 to the Grb2 SH2 domain were determined by ITC (Table 1), and the constrained ligand 2 was observed to bind approximately twofold better than its flexible counterpart 3.…”

α-Lithiated α-Heterosubstituted 2-Alkyloxazolines: Key Players in Organic Synthesis

“…35 The reaction starts with coordination of the methoxy group of the Fischer carbene to the lithium atom of the lithiated epoxide; this is followed by the attack on the re face of the Fischer carbene complex (Scheme 48).…”