Browsing by Subject "Src SH2"
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Item Design and synthesis of conformationally constrained Src SH2 ligands for protein–ligand thermodynamic evaluation(2016-08) Gravenstreter, Alicia Nicole; Martin, Stephen F.; Keatinge-Clay, Adrian TPredicting how small structural changes will impact the thermodynamics of binding a small molecule to a protein represents a major challenge in the fields of drug design and biological recognition. The tetrapeptide, pYEEI, binds to the sarcoma (Src) SH2 domain in both hot spot and non-hot spot locations, presenting an opportunity to examine how ligand preorganization at a non-hot spot region will affect the thermodynamics of binding. Incorporation of a cyclopropane to constrain both the backbone and side-chain of the isoleucine residue of the native pYEEI ligand will allow us to preorganize the ligand in its binding conformation for thermodynamic evaluation. Several attempts towards the preparation of the constrained ligand will be discussed as well as preparation of a flexible control ligand for direct comparison.Item Progress towards the synthesis of succinate-derived flexible peptide for the Src SH2 domain(2012-05) Au, Vincent; Martin, Stephen F.Preorganizing a flexible ligand in the shape it adopts when bound to a protein should theoretically result in an increased binding affinity due to a smaller entropic penalty during binding. Previous work, however, shows that this is not always the case. Constraining the pY residue of a short peptidic sequence, pYEEl, that binds to the Src Homology 2 domain of the Src kinase (Src SH2 domain) resulted in an entropic advantage, but this was offset by an enthalpic penalty that resulted in approximately equal binding affinities of the flexible and constrained ligands. Based on NMR relaxation and molecular dynamics studies of the complex, it is hypothesized that suboptimal interactions within the pY binding site ("binding hot spot") may be the reason for the loss of enthalpy. In order to test this hypothesis, a cyclopropane-derived replacement for the isoleucine residue, which binds to a hydrophobic site of the domain, and its succinate-derived flexible analog are being synthesized. This paper reports the synthesis progress towards the flexible analog.