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Prog Biophys Mol Biol. 2015 Oct;119(1):2-9. doi: 10.1016/j.pbiomolbio.2015.01.009. Epub 2015 Feb 7.

Flexibility and small pockets at protein-protein interfaces: New insights into druggability.

Author information

1
Department of Biochemistry, Sanger Building, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK.
2
Department of Biochemistry, Sanger Building, University of Cambridge, Tennis Court Road, Cambridge CB2 1GA, UK. Electronic address: da382@cam.ac.uk.

Abstract

The transient assembly of multiprotein complexes mediates many aspects of cell regulation and signalling in living organisms. Modulation of the formation of these complexes through targeting protein-protein interfaces can offer greater selectivity than the inhibition of protein kinases, proteases or other post-translational regulatory enzymes using substrate, co-factor or transition state mimetics. However, capitalising on protein-protein interaction interfaces as drug targets has been hindered by the nature of interfaces that tend to offer binding sites lacking the well-defined large cavities of classical drug targets. In this review we posit that interfaces formed by concerted folding and binding (disorder-to-order transitions on binding) of one partner and other examples of interfaces where a protein partner is bound through a continuous epitope from a surface-exposed helix, flexible loop or chain extension may be more tractable for the development of "orthosteric", competitive chemical modulators; these interfaces tend to offer small-volume but deep pockets and/or larger grooves that may be bound tightly by small chemical entities. We discuss examples of such protein-protein interaction interfaces for which successful chemical modulators are being developed.

KEYWORDS:

Hotspots; Inhibitors druggability; Protein–protein interfaces

PMID:
25662442
PMCID:
PMC4726663
DOI:
10.1016/j.pbiomolbio.2015.01.009
[Indexed for MEDLINE]
Free PMC Article

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