Reaching for high-hanging fruit in drug discovery at protein-protein interfaces.

Article Details

Citation

Copy to clipboard

Wells JA, McClendon CL

Reaching for high-hanging fruit in drug discovery at protein-protein interfaces.

Nature. 2007 Dec 13;450(7172):1001-9.

PubMed ID

18075579 [ View in PubMed

]

Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N(2)-carbamimidoyl-N-{2-[4-(3-{4-[(5-carboxyfuran-2-yl)methoxy]-2,3-dichlorophenyl}-1-methyl-1H-pyrazol-5-yl)piperidin-1-yl]-2-oxoethyl}-D-leucinamide	Interleukin-2	Ki (nM)	60	N/A	N/A	Details