In Search of Ras Inhibitors

Abstract

Membrane binding is essential for the biological activity of Ras proteins, the key regulators of diverse signaling pathways whose malfunction accounts for more than 15% of all human tumors and up to 90% of cases in specific tumor types. However, decades of effort has to date failed to yield selective Ras inhibitors. We hypothesize that disrupting the dynamic coupling between the nucleotide-binding and membrane-interacting regions of Ras by small molecule ligands may have better therapeutic potential. As part of an effort to test this hypothesis, we applied a variety of existing and new ligand binding site identification schemes on ensembles of Ras conformers generated by extensive molecular dynamics simulations in solution and membrane environments. We will discuss the discovery of new pockets that have the potential to bind small molecule ligands, along with alternative strategies for Ras drug design emerging from interactions between various computational and experimental approaches.