Inhibition of protein interactions: co-crystalized protein–protein interfaces are nearly as good as holo proteins in rigid-body ligand docking
Modulating protein interaction pathways may lead to the cure of many diseases. Known protein–protein inhibitors bind to large pockets on the protein–protein interface. Such large pockets are detected also in the protein–protein complexes without known inhibitors, making such complexes potentially druggable. The inhibitor-binding site is primary defined by the side chains that form the largest pocket in the protein-bound conformation. Low-resolution ligand docking shows that the success rate for the protein-bound conformation is close to the one for the ligand-bound conformation, and significantly higher than for the apo conformation. The conformational change on the protein interface upon binding to the other protein results in a pocket employed by the ligand when it binds to that interface. This proof-of-concept study suggests that rather than using computational pocket-opening procedures, one can opt for an experimentally determined structure of the target co-crystallized protein–protein complex as a starting point for drug design.
KeywordsMolecular recognition Drug design Conformational properties Molecular modeling Ligand–receptor interaction
This study was supported by National Institutes of Health Grant R01GM074255 and National Science Foundation Grants DBI1262621, DBI1565107 and CNS1337899.
- 7.Basse MJ, Betzi S, Bourgeas R, Bouzidi S, Chetrit B, Hamon V, Morelli X, Roche P (2013) 2P2Idb: a structural database dedicated to orthosteric modulation of protein–protein interactions. Nucl Acid Res 41:D824–D827Google Scholar
- 8.Gorczynski MJ, Grembecka J, Zhou Y, Kong Y, Roudaia L, Douvas MG, Newman M, Bielnicka I, Baber G, Corpora T, Shi J, Sridharan M, Lilien R, Donald BR, Speck NA, Brown ML, Bushweller JH (2007) Allosteric inhibition of the protein-protein interaction between the leukemia-associated proteins Runx1 and CBFβ. Chem Biol 14:1186–1197CrossRefGoogle Scholar
- 10.Acuner Ozbabacan SE, Gursoy A, Keskin O, Nussinov R (2010) Conformational ensembles, signal transduction and residue hot spots: application to drug discovery. Curr Opin Drug Discov Dev 13:527–537Google Scholar
- 31.Liu P, Agrafiotis DK, Theobald DL (2010) Fast determination of the optimal rotational matrix for macromolecular superpositions. J Comput Chem 31:1561–1563Google Scholar