Stabilization of protein–protein interaction complexes through small molecules

• Published in: Drug discovery today Vol. 21; no. 1; pp. 48 - 57
• Main Authors: Zarzycka, Barbara, Kuenemann, Mélaine A., Miteva, Maria A., Nicolaes, Gerry A.F., Vriend, Gert, Sperandio, Olivier
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2016
• Subjects: Biophysical Phenomena - drug effects; Humans; Protein Binding - drug effects; Protein Interaction Maps - drug effects; Small Molecule Libraries - pharmacology
• ISSN: 1359-6446; 1878-5832
• DOI: 10.1016/j.drudis.2015.09.011

•Small molecules.•Stabilizers.•Protein–protein interactions.•Structure-based drug design.•Classification. Most of the small molecules that have been identified thus far to modulate protein–protein interactions (PPIs) are inhibitors. Another promising way to interfere with PPI-associated biological processes is to promote PPI stabilization. Even though PPI stabilizers are still scarce, stabilization of PPIs by small molecules is gaining momentum and offers new pharmacological options. Therefore, we have performed a literature survey of PPI stabilization using small molecules. From this, we propose a classification of PPI stabilizers based on their binding mode and the architecture of the complex to facilitate the structure-based design of stabilizers. The present review proposes a classification of the successfully stabilized protein–protein interactions (PPIs) using small molecules because it represents a new era for PPI modulation that needs to be addressed.