title: Hot spot-based design of small-molecule inhibitors for protein-protein interactions.
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.
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112-0850, USA.
authors.forename: Wenxing
authors.initials: W
authors.lastname: Guo
authors.affiliation: Department of Chemistry, Center for Cell and Genome Science, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112-0850, USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Wisniewski
authors.affiliation: 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.
authors.forename: Haitao
authors.initials: H
authors.lastname: Ji
mesh_terms: D015195:Drug Design; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors*; D054852:Small Molecule Libraries / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011506:Proteins; D054852:Small Molecule Libraries
keywords: Hot spots; Inhibitor; Protein–protein interactions; Rational design; Selectivity