Druggable Protein Interaction Sites Are More Predisposed to Surface Pocket Formation than the Rest of the Protein Surface

By David K. Johnson, John Karanicolas. 2013

88 citations recorded by the source corpus.

Despite intense interest and considerable effort via high-throughput screening, there are few examples of small molecules that directly inhibit protein-protein interactions. This suggests that many protein interaction surfaces may not be intrinsically “druggable” by small molecules, and elevates in importance the few successful examples as model systems for improving our fundamental understanding of druggability. Here we describe an approach for exploring protein fluctuations enriched in conformations containing surface pockets suitable for small molecule binding. Starting from a set of seven unbound protein structures, we find that the presence of low-energy pocket-containing conformations is indeed a signature of druggable protein interaction sites and that analogous surface pockets are not formed elsewhere on the protein. We further find that ensembles of conformations generated with this biased approach structurally resemble known inhibitor-bound structures more closely than equivalent ensembles of unbiased conformations. Collectively these results suggest that “druggability” is a property encoded on a protein surface through its propensity to form pockets, and inspire a model in which the crude features of the predisposed pocket(s) restrict the range of complementary ligands; additional smaller conformational changes then respond to details of a particular ligand. We anticipate that the insights described here will prove useful in selecting protein targets for therapeutic intervention.

Subfields: Computational Theory and Mathematics, Materials Chemistry, Molecular Biology

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Citations in the corpus

DARC 2.0: Improved Docking and Virtual Screening at Protein Interaction Sites (2015, methodology): “(or set of “target” residues) on the protein surface, using a pocket-finding algorithm adapted from the LIGSITE program [23] that we have implemented in the Rosetta software suite [24].”
Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. (2014, background): “Chemistry & Biology 21, September 18, 2014 a virtual methods should allow for sidechain flexibility, since hot spots at these interfaces often show small motions that create deeper binding pockets (Johnson and Karanicolas, 2013; Wells and McClendon, 2007).”
Fast Docking on Graphics Processing Units via Ray-Casting (2013, methodology): “The shape of a surface pocket is defined using a grid-based method described in detail elsewhere [32].”
Selectivity by Small-Molecule Inhibitors of Protein Interactions Can Be Driven by Protein Surface Fluctuations (2015, methodology): “Previously, we found that this method produced ensembles of pocket-containing conformations a slightly higher but overlapping distribution of energies than the unbiased ensemble [14].”