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Features of protein–protein interactions that translate into potent inhibitors: topology, surface area and affinity

Published online by Cambridge University Press:  26 July 2012

Matthew C. Smith  and
Jason E. Gestwicki
Matthew C. Smith
Affiliation:
Departments of Pathology and Biological Chemistry and The Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
Jason E. Gestwicki*
Affiliation:
Departments of Pathology and Biological Chemistry and The Life Sciences Institute, University of Michigan, Ann Arbor, MI, USA
*
*Corresponding author: Jason E. Gestwicki, Departments of Pathology and Biological Chemistry and The Life Sciences Institute, University of Michigan, Life Sciences Institute, 210 Washtenaw Avenue, Ann Arbor, MI 48109-2216, USA. E-mail: gestwick@umich.edu
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Abstract

Protein–protein interactions (PPIs) control the assembly of multi-protein complexes and, thus, these contacts have enormous potential as drug targets. However, the field has produced a mix of both exciting success stories and frustrating challenges. Here, we review known examples and explore how the physical features of a PPI, such as its affinity, hotspots, off-rates, buried surface area and topology, might influence the chances of success in finding inhibitors. This analysis suggests that concise, tight binding PPIs are most amenable to inhibition. However, it is also clear that emerging technical methods are expanding the repertoire of ‘druggable’ protein contacts and increasing the odds against difficult targets. In particular, natural product-like compound libraries, high throughput screens specifically designed for PPIs and approaches that favour discovery of allosteric inhibitors appear to be attractive routes. The first group of PPI inhibitors has entered clinical trials, further motivating the need to understand the challenges and opportunities in pursuing these types of targets.

Type
Review Article
Information
Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e16
Copyright
Copyright © Cambridge University Press 2012

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Further reading

Bourgeas, R. et al. (2010) atomic analysis of protein–protein interfaces with known Inhibitors: the 2p2i database. PLoS One 5, e9598. http://2p2idb.cnrs-mrs.fr/CrossRefGoogle Scholar
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Drewry, D.H. and Macarron, R. (2010) Enhancements of screening collections to address areas of unmet medical need: an industry perspective. Current Opinion in Chemical Biology 14, 289-298CrossRefGoogle ScholarPubMed
Uversky, V.N. (2012) Intrinsically disordered proteins and novel strategies for drug discovery. Expert Opinion on Drug Discovery 7, 475-488CrossRefGoogle ScholarPubMed
Jubb, H., et al. (2012) Structural biology and drug discovery for protein-protein interactions. Trends in Pharmacological Sciences 33(5): 241-248CrossRefGoogle ScholarPubMed
Verdine, G.L. et al. (2012) Chapter one – stapled peptides for intracellular drug targets. In Methods in Enzymology, pp. 3-33. Academic PressGoogle Scholar