Design and synthesis of conformationally constrained ligands for Grb2 SH2 binding and thermodynamic evaluation and the development of a diversity oriented synthesis of 2-arylpiperidines
Goodnough, Alex Michael
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The ways in which torsional strain in the bound form of a ligand affects the energetics of protein binding are poorly understood. In order to study this feature of protein-ligand interactions, a conformationally constrained ligand for Grb2 SH2 containing a 1,1,2 trisubstituted cyclopropane was designed, and the synthesis of this ligand attempted. Additionally, a novel iminium ion formation/cyclization cascade was applied to the synthesis of a library of 2-arylpiperidines with varying aryl group substitution, and nitrogen atom functionalization. This strategy should allow further access to chemical space already identified as containing potential therapeutics and tool compounds for biological interrogation.