Journal
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
Volume 32, Issue 7, Pages 769-779Publisher
SPRINGER
DOI: 10.1007/s10822-018-0124-z
Keywords
Molecular recognition; Drug design; Conformational properties; Molecular modeling; Ligand-receptor interaction
Categories
Funding
- National Institutes of Health [R01GM074255]
- National Science Foundation [DBI1262621, DBI1565107, CNS1337899]
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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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