Druggable Orthosteric and Allosteric Hot Spots to Target Protein-protein Interactions

Title:Druggable Orthosteric and Allosteric Hot Spots to Target Protein-protein Interactions

Volume: 20 Issue: 8

Author(s): Buyong Ma and Ruth Nussinov

Affiliation:

Keywords: Drug discovery, allosteric drugs, protein binding site, allostery, amyloid, protein-protein interfaces, protein pockets.

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.

Cite this article as:

Ma Buyong and Nussinov Ruth, Druggable Orthosteric and Allosteric Hot Spots to Target Protein-protein Interactions, Current Pharmaceutical Design 2014; 20 (8) . https://dx.doi.org/10.2174/13816128113199990073