Journal of Computer-Aided Molecular Design

, Volume 32, Issue 7, pp 769–779 | Cite as

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

  • Saveliy Belkin
  • Petras J. Kundrotas
  • Ilya A. Vakser


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.


Molecular 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.

Supplementary material

10822_2018_124_MOESM1_ESM.pdf (2.2 mb)
Supplementary material 1 (PDF 2298 KB)


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Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Center for Computational BiologyThe University of KansasLawrenceUSA
  2. 2.Department of Molecular BiosciencesThe University of KansasLawrenceUSA

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