Identification of druggable hot spots on proteins and in protein- protein interfaces

The interactions of proteins with each other and other biochemical compounds play a central role in various aspects of the structural and functional organization of the cell. Elucidation of such interactions is a major step toward understanding cellular pathways and processes and also suggests avenues for drug design. One observation that emerges from these studies is that the various residues in the binding region do not equally contribute to the binding free energy. By replacing individual interface residues with alanine (known as alanine scanning mutagenesis), Clackson and Wells found that a central hydrophobic region of human growth hormone receptor accounts for more than three-quarters of the binding free energy. This led the authors to introduce the notion of hot spots.