Druggable Orthosteric and Allosteric Hot Spots to Target Protein-protein Interactions
Buyong Ma and Ruth Nussinov
Pages 1293-1301 (9)
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.
Drug discovery, allosteric drugs, protein binding site, allostery, amyloid, protein-protein interfaces, protein pockets.
Basic Science Program, Leidos Biomedical Research, Inc. Cancer and Inflammation Program, NCIFrederick, Frederick, MD 21702.