Druggability of Dynamic Protein-protein Interfaces

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SELECTBIO

The conformational flexibility of protein targets is being increasingly recognized in the drug discovery and design processes. When working on a particular disease-related biochemical pathway, it is of crucial importance to carefully select druggable protein binding pockets among all those cavities that may appear transiently or permanently on the respective protein surface. We will look into how the conformational dynamics of proteins governs the formation and disappearance of such transient pockets on protein surfaces. Interestingly, we observed in molecular dynamics simulations of the proteins MDM2, IL-2, Bcl-XL, the XIAP Bir2 domain, and PDK1 in their apo forms that conformational transitions on the protein surface leading to the frequent formation of transition pockets occur almost barrierless. Large pockets are found at similar frequencies as small pockets. Ligand docking confirmed that these pockets are suitable to bind known ligand molecules. We will illustrate how the identified pockets depend on the way in which corresponding pockets in different molecular dynamics snapshots are connected to each other. With respect to the druggability of transiently formed pockets, protein cavities suitable to bind small drug-like molecules showed an increased pocket size and buriedness when compared to empty sites.