Protein scaffold inhibition12/19/2023 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. Thus, it seems important to choose the inhibitor scaffold based on the properties of the target interaction. PPIs with BSA values over 4000 Å 2 seemed to create a particular challenge, especially for orthosteric small molecules. Finally, we found PPIs with buried surface area (BSA) less than 2000 Å 2 were more likely to be inhibited by small molecules, while PPIs with larger BSA values were typically inhibited by peptides. 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 < 1 μM). From the 66 recently reported PPI inhibitors, we found that the average molecular weight was significantly greater than 500 Da, but that this trend was driven, in large part, by the contribution of peptide-based compounds. Our findings suggest that surface loops of protease and scaffold stability of Kazal-type inhibitor are both necessary for specific protease inhibition, in addition to. Here, we review the last three years of literature on PPI inhibitors to understand what is working and why. Protein Science, the flagship journal of The Protein Society, serves an international forum for publishing original reports on all scientific aspects of protein molecules. Protein–protein interactions (PPI) were once considered ‘undruggable’, but clinical successes, driven by advanced methods in drug discovery, have challenged that notion.
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