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Review
. 2015 Dec:35:78-85.
doi: 10.1016/j.copbio.2015.04.006. Epub 2015 May 15.

Alternative modulation of protein-protein interactions by small molecules

Gerhard Fischer  1 , Maxim Rossmann  1 , Marko Hyvönen  2
Affiliations
Review

Alternative modulation of protein-protein interactions by small molecules

Gerhard Fischer et al. Curr Opin Biotechnol. 2015 Dec.

Abstract

Protein-protein interactions (PPI) have become increasingly popular drug targets, with a number of promising compounds currently in clinical trials. Recent research shows, that PPIs can be modulated in more ways than direct inhibition, where novel non-competitive modes of action promise a solution for the difficult nature of PPI drug discovery. Here, we review recently discovered PPI modulators in light of their mode of action and categorise them as disrupting versus stabilising, orthosteric versus allosteric and by their ability to affect the proteins' dynamics. We also give recent examples of compounds successful in the clinic, analyse their physicochemical properties and discuss how to overcome the hurdles in discovering alternative modes of modulation.

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Figures

None
Graphical abstract
Figure 1
Figure 1
Binding modes of modulators (orange) influencing PPIs. The affinity of two proteins (blue/grey) can be decreased by either orthosteric (a) or allosteric disruption (b), while stabilisation can occur through binding at a composite site formed by the protein complex (c) or allosterically (d). Note that all binding modes but (a) are non-competitive in nature.
Figure 2
Figure 2
Schematic representation of secondary effects of interfacial binders through protein dynamics. (a) An interfacial binder affecting the oligomerisation of the protein complex, similar to HIV-integrase (see text). (b) An interfacial binder allosterically changing the functionality of the protein's active site.
Figure 3
Figure 3
Examples for PPI modulation. The small molecules are represented as a space filling model in orange, the individual proteins in blue and grey. (a) Dimer of transthyretin stabilised by two molecules of Tafamidis (PDB: 3tct). (b) RVX-208 bound to the monomer of BRD2(BD2), preventing interaction with peptide ligand (PDB: 4mr6). (c) Allosteric stabilisation of the Cdc34–Ubiquitin interaction through small molecule CC0651 (PDB: 4mdk). (d) Allosteric destabilisation of the KRas–Sos–interaction through a covalently attached inhibitor (PDB: 4lv6). The image is a superpositioning of the apo-KRas/Sos-complex and the KRas-ligand complex. (e) Allosteric inhibitor at the interface of a DHPS-dimer, affecting its intramolecular dynamics (PDB: 4nhv).
See this image and copyright information in PMC

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