Approximately 30% of all human cancers are associated with malfunction in Ras proteins. However, Ras is such an elusive drug target that there are currently no drugs that directly bind Ras and inhibit its abnormal function. Using a multi-level computational approach that involves ensembles of Ras structures derived from both experiment and molecular dynamics simulation, ligand-based pocket identification schemes and ensemble docking, we identified a number of small molecule hits that bind to allosteric sites of Ras and exhibit inhibitory activities in Ras-driven cancer cells. These putative ligands preferentially target pockets that transiently open either near switch 1 and switch 2 or at a distal site proximal to the C-terminal membrane-interacting region. We will discuss the potential of these ligands to serve as leads for a novel therapeutic strategy to prevent abnormal Ras signaling.

Towards the identification of small molecule Ras inhibitors: A dynamics-guided approach

245th National Meeting (2013)

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