Structure-Based Design and Solid-Phase Parallel Synthesis of Phosphorylated Nonpeptides to Explore Hydrophobic Binding at the Src SH2 Domain

Abstract

Using a novel, solid-phase parallel synthetic route and a computational docking program, a series of phosphorylated nonpeptides were generated to determine their structure-activity relationships (SAR) for binding at the SH2 domain of pp60src (Src). A functionalized benzoic acid intermediate was attached to solid support via Rink amide linkage, which upon acid cleavage generated the desired benzamide template-based nonpeptides in a facile manner. Compounds were synthesized using a combination of solid- and solution-phase techniques. Purification using reversed-phase, semipreparative HPLC allowed for quantitative SAR studies. Specifically, this work focused on functional group modifications, in a parallel fashion, designed to explore hydrophobic binding at the pY+3 pocket of the Src SH2 domain.

Protein–protein interactions: mechanisms and modification by drugs

“…Numerous investigations have been done in an attempt to design IDs for proteins possessing stable domains, which interact with receptors: SH2 domain (Alligood et al, 1998;Beaulieu et al, 1999;Burke et al, 1999Burke et al, , 2001Cody et al, 2000;Davidson and Martin, 2000;Eaton et al, 1998;Fretz et al, 2000;Furet et al, 1999Furet et al, , 2000Gao et al, 2000;Gay et al, 1999a,b;Garciaecheverria, 2001;Hart et al, 1999;Kim et al, 1999;Lou et al, 1999;Metcalf et al, 2000;Niimi et al, 2001;Pacofsky et al, 1998;Rickles et al, 1998;Schoepfer et al, 1998Schoepfer et al, , 1999Shakespeare, 2001;Shakespeare et al, 2000;Violette et al, 2000;Vu, 2000;Vu et al, 1999;Walker et al, 2000;Yao et al, 1999), SH3 domain (Dalgarno et al, 1997;Nguyen et al, 2000;Witter et al, 1998) and PDZ domain (Fuh et al, 2000).…”

High Throughput Chemistry in Drug Discovery

“…For example, Metcalf et al used solid-phase syntheses and computational docking approaches to develop SAR around the hydrophobic binding pockets of the Src SH2 domain. 135 In particular, the group made use of a conserved binding motif of a primary carboxamide as a handle for solid-phase chemistry of a range of phosphorylated aryl alkoxides (Scheme 2.13).…”

Design and Synthesis of Protein Superfamily-Targeted Chemical Libraries for Lead Identification and Optimization

“…While these compounds displayed high potency as both cathepsin B and S inhibitors, the incorporation of a bulky aliphatic residue as the P 1 position of the dipeptide motif led to the identification of analogues with high selectivity for cathepsin S, of which compound (171) was the most potent inhibitor [228].…”