Features of protein-protein interactions that translate into potent inhibitors: topology, surface area and affinity

Abstract

Protein-protein interactions (PPIs) control the assembly of multi-protein complexes and, thus, these contacts have enormous potential as drug targets. However, the field has produced a mix of both exciting success stories and frustrating challenges. Here, we review known examples and explore how the physical features of a PPI, such as its affinity, hotspots, off-rates, buried surface area and topology, might influence the chances of success in finding inhibitors. This analysis suggests that concise, tight binding PPIs are most amenable to inhibition. However, it is also clear that emerging technical methods are expanding the repertoire of 'druggable' protein contacts and increasing the odds against difficult targets. In particular, natural product-like compound libraries, high throughput screens specifically designed for PPIs and approaches that favour discovery of allosteric inhibitors appear to be attractive routes. The first group of PPI inhibitors has entered clinical trials, further motivating the need to understand the challenges and opportunities in pursuing these types of targets.

Figure 1. Categorization of protein-protein interactions (PPIs) and their inhibitors

PPIs with known inhibitors were from obtained from the 2P2I (Ref. 10) and TIMBAL (Ref. 50) databases and recent literature. These PPIs were then categorized by the affinity (K_D) of the protein-protein interaction and the buried surface area from co-crystal structures (see Table 1). These values were used to arbitrarily categorize the “inhibit-able” PPIs into four quadrants. To illustrate the types of proteins in each category, structures of representative PPIs from each class are shown, with each partner depicted in either blue or red. For “Tight and Wide” the interaction is between the armadillo repeat region of β-catenin and the catenin binding domain of Xenopus TCF3 (PDB: 1G3J). For “Tight and Narrow” the interaction is between IL-2 and the IL-2α Receptor (PDB: 1Z92). For “Loose and Narrow” the interaction is between TPR1 and a C-terminal peptide of Hsc70 (PDB: 1ELW) and for “Loose and Wide” the interaction is between Ras and SOS (PDB: 1BKD). Also shown are 19 representative chemical structures of the PPI inhibitors, illustrating the lack of consensus in molecular weight, shape or other characteristics.

Figure 2. Average potency of inhibitors in each class of protein-protein interaction

The most potent inhibitors published for each interaction listed in Table 1 were averaged within the four PPI categories. The category of “Loose and Wide” did not have enough examples to be included.

Figure 3. Inhibition of protein-protein interactions in the chaperone complexes

Complexes between Hsp70 and Hsp90 and their co-chaperones are shown. PES 13 inhibits the Hsp70/Bag1 interaction, myricetin 14 inhibits the Hsp70/Hsp40 interaction, celastrol 17 inhibits Hsp90/cdc37, and San A 18 inhibits the Hsp90/TPR interactions. Abbreviations: NEF, nucleotide exchange factor; TPR, tetratricopeptide repeat domain-containing co-chaperone; San A, sansalvamide A.