Article

Journal of Computer-Aided Molecular Design

, Volume 20, Issue 2, pp 109-130

Development of small molecules designed to modulate protein–protein interactions

  • Ye CheAffiliated withLaboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health Email author 
  • , Bernard R. BrooksAffiliated withLaboratory of Computational Biology, National Heart, Lung and Blood Institute, National Institutes of Health
  • , Garland R. MarshallAffiliated withCenter for Computational Biology and Department of Biochemistry and Molecular Biophysics, Washington University

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Summary

Protein–protein interactions are ubiquitous, essential to almost all known biological processes, and offer attractive opportunities for therapeutic intervention. Developing small molecules that modulate protein–protein interactions is challenging, owing to the large size of protein-complex interface, the lack of well-defined binding pockets, etc. We describe a general approach based on the “privileged-structure hypothesis” [Che, Ph.D. Thesis, Washington University, 2003] – that any organic templates capable of mimicking surfaces of protein-recognition motifs are potential privileged scaffolds as protein-complex antagonists – to address the challenges inherent in the discovery of small-molecule inhibitors of protein–protein interactions.

Keywords

conformational analysis drug design peptidomimetics protein–protein interaction protein-surface mimetics privileged scaffold template design