Strategies to search and design stabilizers of protein-protein interactions: a feasibility study

Since protein-protein interactions play a pivotal role in the communication on the molecular level in virtually every biological system and process, the search and design for modulators of such interactions is of utmost importance. In recent years many inhibitors for specific protein-protein interactions have been developed, however, in only a few cases, small and druglike molecules are able to interfere in the complex formation of proteins. On the other hand, there are several small molecules known to modulate protein-protein interactions by means of stabilizing an already assembled complex. To achieve this goal, a ligand is binding to a pocket, which is located rim-exposed at the interface of the interacting proteins, for example as the phytotoxin Fusicoccin, which stabilizes the interaction of plant H+-ATPase and 14-3-3 protein by nearly a factor of 100. To suggest alternative leads, we performed a virtual screening campaign to discover new molecules putatively stabilizing this complex. Furthermore, we screen a dataset of 198 transient recognition protein-protein complexes for cavities, which are located rim-exposed at their interfaces. We provide evidence for high similarity between such rim-exposed cavities and usual ligands accommodating active sites of enzymes. This analysis suggests that rim-exposed cavities at protein-protein interfaces are druggable binding sites. Therefore, the principle of stabilizing protein-protein interactions seems to be a promising alternative to the approach of the competitive inhibition of such interactions by small molecules.