title: Druggable protein interaction sites are more predisposed to surface pocket formation than the rest of the protein surface.
abstract: 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.
authors.affiliation: Center for Bioinformatics, University of Kansas, Lawrence, Kansas, United States of America.
authors.forename: David K
authors.initials: DK
authors.lastname: Johnson
authors.forename: John
authors.initials: J
authors.lastname: Karanicolas
mesh_terms: D001665:Binding Sites; D019295:Computational Biology / Q000379:methods*; D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods*; D051034:Inhibitor of Apoptosis Proteins / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013499:Surface Properties; D051020:bcl-X Protein / Q000737:chemistry
chemical_list: D051034:Inhibitor of Apoptosis Proteins; D011506:Proteins; D051020:bcl-X Protein