Volume 51, Issue 9
Minireview

Small‐Molecule Stabilization of Protein–Protein Interactions: An Underestimated Concept in Drug Discovery?

Dipl.‐Bioinf. Philipp Thiel

Chemical Genomics Centre of the Max Planck Society, Otto‐Hahn‐Strasse 15, 44227 Dortmund (Germany) http://www.cgc.mpg.de

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Prof. Dr. Markus Kaiser

Centre for Medical Biotechnology, Faculty of Biology, Universität Duisburg‐Essen, Universitätsstrasse 2, 45141 Essen (Germany)

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Dr. Christian Ottmann

Corresponding Author

E-mail address: [email protected]

Chemical Genomics Centre of the Max Planck Society, Otto‐Hahn‐Strasse 15, 44227 Dortmund (Germany) http://www.cgc.mpg.de

Chemical Genomics Centre of the Max Planck Society, Otto‐Hahn‐Strasse 15, 44227 Dortmund (Germany) Search for more papers by this author
First published: 03 February 2012
Citations: 116

In the general annotations to presented structure figures, SES is the solvent‐excluded surface, and highlighted interaction surfaces are defined as surface patches within a distance of 3.5 Å next to the binding partner. All representations were generated with BALLView. 1

Abstract

The modulation of protein–protein interactions (PPIs) has been recognized as one of the most challenging tasks in drug discovery. While their systematic development has long been considered as intractable, this view has changed over the last years, with the first drug candidates undergoing clinical studies. To date, the vast majority of PPI modulators are interaction inhibitors. However, in many biological contexts a prolonged lifespan of a PPI might be desirable, calling for the complementary approach of PPI stabilization. In fact, nature offers impressive examples of this concept and some PPI‐stabilizing natural products have already found application as important drugs. Moreover, directed small‐molecule stabilization has recently been demonstrated. Therefore, it is time to take a closer look at the constructive side of modulating PPIs.

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