Plucking the high hanging fruit: a systematic approach for targeting protein-protein interactions

Abstract

Development of specific ligands for protein targets that help decode the complexities of protein-protein interaction networks is a key goal for the field of chemical biology. Despite the emergence of powerful in silico and experimental high-throughput screening strategies, the discovery of synthetic ligands that selectively modulate protein-protein interactions remains a challenge for bioorganic and medicinal chemists. This Perspective discusses emerging principles for the rational design of PPI inhibitors. Fundamentally, the approach seeks to adapt nature's protein recognition principles for the design of suitable secondary structure mimetics.

Figure 1

Protein-protein interactions are often mediated by secondary structures: (a) α-helical and (b) β-sheet interfaces from barnase_barstar (PDB code: 1BGS) and Raf-Rap (PDB code: 1GUA), respectively.

Figure 2

Helical interfaces can be divided between those that feature clefts for binding and those with extended interfaces. The cleft interfaces may be compared to enzyme pockets in that a high density of important contacts is concentrated in a small region. The Gleevek/tyrosine kinase (PDB code: 1XBB), p53/MDM2 (PDB code: 1YCR) and cyclin- dependent kinase6/D-type viral cyclin (PDB code: 1G3N) complexes are representative examples of enzyme pockets, binding cleft and extended interfaces, respectively.

Figure 3

(a) Positioning of side-chain residues on a canonical α-helix. (b–d) examples of protein complexes with hot spot residues on one face, two faces, and three faces. (b) Yersinia pestis YopN/TyeA complex, PDB code 1XL3; (c) ligand-binding domain (LBD) of the retinoid X receptor/coactivator complex (PDB code 1XIU); (d) E. coli sigma factor/anti-sigma RseA complex, PDB code 1OR7.