Inhibition of protein interactions: co-crystalized protein–protein interfaces are nearly as good as holo proteins in rigid-body ligand docking

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Issue Date
2018-07-12Author
Belkin, Saveliy
Kundrotas, Petras J.
Vakser, Ilya A.
Publisher
Springer International Publishing
Type
Article
Article Version
Scholarly/refereed, author accepted manuscript
Rights
© Springer International Publishing AG, part of Springer Nature 2018
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Show full item recordAbstract
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.
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Citation
Belkin, S., Kundrotas, P. J., & Vakser, I. A. (2018). Inhibition of protein interactions: co-crystalized protein-protein interfaces are nearly as good as holo proteins in rigid-body ligand docking. Journal of computer-aided molecular design, 32(7), 769–779. doi:10.1007/s10822-018-0124-z
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