Hot spot-based design of small-molecule inhibitors for protein-protein interactions

Wenxing Guo; John A Wisniewski; Haitao Ji

doi:10.1016/j.bmcl.2014.03.095

Hot spot-based design of small-molecule inhibitors for protein-protein interactions

Bioorg Med Chem Lett. 2014 Jun 1;24(11):2546-54. doi: 10.1016/j.bmcl.2014.03.095. Epub 2014 Apr 5.

Authors

Wenxing Guo¹, John A Wisniewski¹, Haitao Ji²

Affiliations

¹ Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112-0850, USA.
² Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112-0850, USA. Electronic address: markji@chem.utah.edu.

PMID: 24751445
DOI: 10.1016/j.bmcl.2014.03.095

Abstract

Protein-protein interactions (PPIs) are important targets for the development of chemical probes and therapeutic agents. From the initial discovery of the existence of hot spots at PPI interfaces, it has been proposed that hot spots might provide the key for developing small-molecule PPI inhibitors. However, there has been no review on the ways in which the knowledge of hot spots can be used to achieve inhibitor design, nor critical examination of successful examples. This Digest discusses the characteristics of hot spots and the identification of druggable hot spot pockets. An analysis of four examples of hot spot-based design reveals the importance of this strategy in discovering potent and selective PPI inhibitors. A general procedure for hot spot-based design of PPI inhibitors is outlined.

Keywords: Hot spots; Inhibitor; Protein–protein interactions; Rational design; Selectivity.

MeSH terms

Drug Design*
Models, Molecular
Molecular Structure
Protein Binding / drug effects
Proteins / antagonists & inhibitors*
Small Molecule Libraries / chemical synthesis
Small Molecule Libraries / chemistry
Small Molecule Libraries / pharmacology*

Substances

Proteins
Small Molecule Libraries