Design and synthesis of conformationally constrained Src SH2 ligands for protein–ligand thermodynamic evaluation

Predicting 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.