Small molecules, big targets: drug discovery faces the protein-protein interaction challenge

Nat Rev Drug Discov. 2016 Aug;15(8):533-50. doi: 10.1038/nrd.2016.29. Epub 2016 Apr 11.


Protein-protein interactions (PPIs) are of pivotal importance in the regulation of biological systems and are consequently implicated in the development of disease states. Recent work has begun to show that, with the right tools, certain classes of PPI can yield to the efforts of medicinal chemists to develop inhibitors, and the first PPI inhibitors have reached clinical development. In this Review, we describe the research leading to these breakthroughs and highlight the existence of groups of structurally related PPIs within the PPI target class. For each of these groups, we use examples of successful discovery efforts to illustrate the research strategies that have proved most useful.

Publication types

  • Review

MeSH terms

  • Animals
  • Computational Biology
  • Drug Discovery / trends*
  • Humans
  • Models, Molecular
  • Protein Interaction Domains and Motifs / drug effects*
  • Protein Structure, Tertiary
  • Proteins / chemistry
  • Proteins / drug effects*
  • Small Molecule Libraries


  • Proteins
  • Small Molecule Libraries