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<1μM). Finally, we found PPIs with buried surface area (BSA) less than 2000Å 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 4000Å 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.

Structural basis of polyethylene glycol recognition by antibody

“…The 2B5 Fab has about 575 Å 2 surface area buried, 405 Å 2 on the heavy chain and 170 Å 2 on the light chain, involving more than 9 and 6 residues, respectively. Although in both cases the Fab-Fab interface is significantly smaller than most other protein-protein interaction (PPI) areas that range from 1200 Å 2 to 2000 Å 2 , it is comparable to those in the active-site-like PPI for transient docking [24,25]. Presumably the Fab dimers of 3.3 and 2B5 do not form spontaneously in the absence of PEG.…”

PDZ Domains as Drug Targets

“…[8] This view is now changing since several PPI modulators, binding with high affinity, have been approved as medicines. [90] This strategy has been successfully used to design high-affinity PDZ inhibitors toward neurological and also cancer targets, and one of these ligands has reached late-stage clinical trials. [90] This strategy has been successfully used to design high-affinity PDZ inhibitors toward neurological and also cancer targets, and one of these ligands has reached late-stage clinical trials.…”

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

“…As previously stated, APOE, especially APOE4, is normally found within Aβ deposits [141]. Inhibitors of protein-protein interactions (PPI), once considered undruggable, are now emerging as a tour de force because of dramatic improvement in understanding of PPI scaffold chemistry [142]. An advantage of this method is that these are often naturally occurring molecules that can be very selective because of their precise targeting [143].…”