Protein–Protein Interactions as Drug Discovery Targets

Abstract

Protein–protein interactions (PPIs) recently have been recognized as a major class of drug targets. Many of the successful “classical” biotechnology protein drugs are agonists or antagonists of PPIs and there are established pathways for their development. However, small molecular weight compounds as antagonists of PPIs still pose a major problem to discovery due to the inherent physicochemical properties of their targets. Recently, several small molecular weight antagonists of PPIs advanced into clinical trials and thus comprise a proof-of-concept to this young area in medicinal chemistry. This chapter summarizes the area of small molecular weight antagonists of PPIs with a focus on recent success stories. After a short introduction into the structural biology of PPIs, recognized important PPI targets, discovery pathways of their inhibitors are discussed. The PPI p53-Mdm2 with potential applications in cancer is used as a case study to demonstrate to diversity of approaches leading to many different lead structures. In contrast, the discovery of IL-2/IL-2 rec. antagonists is discussed to highlight adaptive high affinity binding to hotspot regions. Keywords: computational docking; drug discovery target; FBA; HTS; PPI; protein–protein interaction