Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area

Abstract

Protein-protein interactions (PPI) were once considered 'undruggable', but clinical successes, driven by advanced methods in drug discovery, have challenged that notion. Here, we review the last three years of literature on PPI inhibitors to understand what is working and why. From the 66 recently reported PPI inhibitors, we found that the average molecular weight was significantly greater than 500Da, but that this trend was driven, in large part, by the contribution of peptide-based compounds. Despite differences in average molecular weight, we found that compounds based on small molecules or peptides were almost equally likely to be potent inhibitors (K_D<1μM). Finally, we found PPIs with buried surface area (BSA) less than 2000Ų were more likely to be inhibited by small molecules, while PPIs with larger BSA values were typically inhibited by peptides. PPIs with BSA values over 4000Ų seemed to create a particular challenge, especially for orthosteric small molecules. Thus, it seems important to choose the inhibitor scaffold based on the properties of the target interaction. Moreover, this survey suggests a (more nuanced) conclusion to the question of whether PPIs are good drug targets; namely, that some PPIs are readily 'druggable' given the right choice of scaffold, while others still seem to deserve the 'undruggable' moniker.

Figure 1

Schematic properties of PPI inhibitors. (A) Small molecules or peptides can inhibit PPIs by binding to the interface (orthosteric) or a distal site (allosteric). Peptides are often derived from natural protein partners and can be either structured (e.g. helical) or disordered (e.g. random coil). (B) Categorization of PPIs based on buried surface area (BSA) and the affinity of the PPI creates four types of interactions. In the last 20+ years of PPI inhibitor discovery, the majority of reported inhibitors have been directed at the concise/strong qudrant (bottom left). These compounds also tend to have the best potency values.See the text for references.

Figure 2

Targets, disease indications and chemical structures of select small molecule PPI inhibitors

Figure 3

Targets, disease indications and chemical structures of select peptide-based PPI inhibitors

Figure 4

Relative properties and composition of the technologies used to target PPIs (reported 1/15 to 3/18). (A)The average molecular mass of the three categories of PPI inhibitors. Error bars represent the standard error of the mean (SEM). The dotted line is set to 500 Da. * monobody excluded (B) The relative contriibution of the three inhibitor categories, calculated from the 66 literature examples with reported Kd/Ki value. (B) An analysis of the subset of 40 cases that have reported Kd/Ki values < 1 μM. (D) Distribution of PPI inhibitors based on their molecular weight and BSA of the target interface. The red box signifies the most drug-like inhibitors (e.g. those with the lowest mass and best potency). (E) Distribution of recent PPI inhibitors (1/15 to 3/18). Each compound was manually designated as either a small molecule, peptide or miscellaneous. In addition, the mechanism-of-action was designated as orthosteric (solid color) or allosteric (split color). For each compound, its potency (Kd or Ki) was plotted against buried surface area (BSA) of the target PPI. The bottom two quadrants (the most potent molecules) are shown as close-ups for clarity.