Reaching for high-hanging fruit in drug discovery at protein-protein interfaces.
Targeting the interfaces between proteins has huge therapeutic potential, but discovering small-molecule drugs that disrupt protein-protein interactions is an enormous challenge. Several recent success stories, however, indicate that protein-protein interfaces might be more tractable than has been thought. These studies discovered small molecules that bind with drug-like potencies to 'hotspots' on the contact surfaces involved in protein-protein interactions. Remarkably, these small molecules bind deeper within the contact surface of the target protein, and bind with much higher efficiencies, than do the contact atoms of the natural protein partner. Some of these small molecules are now making their way through clinical trials, so this high-hanging fruit might not be far out of reach.
Wells
James A
JA
Department of Pharmaceutical Chemistry, University of California at San Francisco, 1700 4th Street 503A, San Francisco, California 94156, USA. jim.wells@ucsf.edu
McClendon
Christopher L
CL
D000818:Animals; D001665:Binding Sites; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006801:Humans; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*
D011506:Proteins