Rational modulator design by exploitation of protein–protein complex structures

Abstract

The horizon of drug discovery is currently expanding to target and modulate protein–protein interactions (PPIs) in globular proteins and intrinsically disordered proteins that are involved in various diseases. To either interrupt or stabilize PPIs, the 3D structure of target protein–protein (or protein–peptide) complexes can be exploited to rationally design PPI modulators (inhibitors or stabilizers) through structure-based molecular design. In this review, we present an overview of experimental and computational methods that can be used to determine 3D structures of protein–protein complexes. Several approaches including rational and in silico methods that can be applied to design peptides, peptidomimetics and small compounds by utilization of determined 3D protein–protein/peptide complexes are summarized and illustrated.