Identification of Secondary Binding Sites on Protein Surfaces for Rational Elaboration of Synthetic Protein Mimics

Minimal mimics of protein conformations provide rationally designed ligands to modulate protein function. The advantage of minimal mimics is that they can be chemically synthesized and coaxed to be proteolytically resistant; a key disadvantage is that minimization of the protein binding epitope may be associated with loss of affinity and specificity. Several approaches to overcome this challenge may be envisioned, including deployment of covalent warheads and use of nonnatural residues to improve contacts with the binding surface. Herein, we describe our computational and experimental efforts to enhance the minimal protein mimics with fragments that can contact undiscovered binding pockets on Mdm2 and MdmX - two well-studied protein partners of p53.