Structural conservation of druggable hot spots in protein-protein interfaces.

ABSTRACT: Despite the growing number of examples of small-molecule inhibitors that disrupt protein-protein interactions (PPIs), the origin of druggability of such targets is poorly understood. To identify druggable sites in protein-protein interfaces we combine computational solvent mapping, which explores the protein surface using a variety of small "probe" molecules, with a conformer generator to account for side-chain flexibility. Applications to unliganded structures of 15 PPI target proteins show that the druggable sites comprise a cluster of binding hot spots, distinguishable from other regions of the protein due to their concave topology combined with a pattern of hydrophobic and polar functionality. This combination of properties confers on the hot spots a tendency to bind organic species po

SUBMITTER: Kozakov D 

PROVIDER: S-EPMC3158149 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature