title: Druggable orthosteric and allosteric hot spots to target protein-protein interactions.
abstract: Drug designing targeting protein-protein interactions is challenging. Because structural elucidation and computational analysis have revealed the importance of hot spot residues in stabilizing these interactions, there have been on-going efforts to develop drugs which bind the hot spots and out-compete the native protein partners. The question arises as to what are the key 'druggable' properties of hot spots in protein-protein interactions and whether these mimic the general hot spot definition. Identification of orthosteric (at the protein- protein interaction site) and allosteric (elsewhere) druggable hot spots is expected to help in discovering compounds that can more effectively modulate protein-protein interactions. For example, are there any other significant features beyond their location in pockets in the interface? The interactions of protein-protein hot spots are coupled with conformational dynamics of protein complexes. Currently increasing efforts focus on the allosteric drug discovery. Allosteric drugs bind away from the native binding site and can modulate the native interactions. We propose that identification of allosteric hot spots could similarly help in more effective allosteric drug discovery. While detection of allosteric hot spots is challenging, targeting drugs to these residues has the potential of greatly increasing the hot spot and protein druggability.
authors.forename: Buyong
authors.initials: B
authors.lastname: Ma
authors.affiliation: Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, NCIFrederick, Frederick, MD 21702. mabuyong@mail.nih.gov.
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D000494:Allosteric Regulation; D000495:Allosteric Site; D019295:Computational Biology; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry*; D036081:Receptors, Eph Family / Q000737:chemistry; D018631:ras Proteins / Q000737:chemistry
chemical_list: D008024:Ligands; D010455:Peptides; D011506:Proteins; D036081:Receptors, Eph Family; D018631:ras Proteins