Detection of transient pockets on protein surfaces as putative inhibitor binding pockets.
Researcher of this topic is: Susanne Eyrisch
Problems in structure-based drug design of protein-protein interaction inhibitors
Traditional structure-based drug design relies on the availability of an experimental high-resolution protein crystal structure. Based on these structure ligands may be docked by virtual screening packages into cavities of suitable size on the protein surface in order to identify potential drug candidates for in-vitro screening. The crystal structures of protein-protein complexes, however, often lack deep clefts or clearly shaped binding pockets at the interface regions. Therefore, the structure-based design of inhibitors of protein-protein interactions is generally considered to be quite difficult.
Detection of transient pockets on protein surfaces
The aim of our study is to provide a starting point for in-silico drug design for cases in which standard screening methods would fail, for example when no potential binding pocket could be identified. We developed a new pocket detection protocol that successfully identified transient pockets on the protein surfaces of BCL-XL, IL-2, and MDM2. As the native inhibitor binding pocket was absent or only partly detectable in the unbound proteins, these crystal structures were used as starting points for 10 ns long molecular dynamics simulations. Trajectory snapshots were scanned for cavities on the protein surface using the program PASS [Brady, Stouten. J. Comput. Aided Mol. Des. 2000]. The detected cavities were clustered to determine several distinct transient pockets. At the native binding site, pockets of similar size as with a known inhibitor bound could be observed for all three systems. AutoDock [Morris et al. J. Comput. Chem. 1998] could successfully place inhibitor molecules into these transient pockets with less than 2 Å RMS deviation from their crystal structures suggesting this protocol as a viable tool to identify transient ligand binding pockets on protein surfaces.
Eyrisch, S. and Helms, V. (2007) Journal of Medicinal Chemistry, Vol. 50, p. 3457-3464. .