Computational design of novel PROTAC structures targeting the KRAS pathway

In healthy cells, KRAS is an on/off switch that regulates cell growth by binding GTP, which is then converted to GDP. KRAS can, however, become fixed in the "on" position when the gene is mutated, resulting in uncontrolled cell growth. Although mutant KRAS has been extensively studied and is prevalent in cancer, it remains a challenging therapeutic target due to the lack of traditional druggable pockets on its surface. Recent discoveries of potent covalent inhibitors of the KRASG12C mutant have sparked new interest in small molecules targeting KRAS. It is in this context that Proteolysis TArgeting Chimeras (PROTACs) a new and promising method for drug discovery presents itself as one possible solution. This bifunctional molecule forms a ternary complex with a protein of interest (POI) and an E3 ligase, allowing the E3 ligase to ubiquitinate the POI at its proximal lysine residues. The 26S proteasome recognizes and degrades ubiquitinated POI. In the present study, a kinetic model is developed to clarify certain aspects of the protac’s functioning and is aimed at the design of a novel chemical entity using a combination of a KRAS inhibitor, a linker molecule and a new E3 ligase-binding compound discovered earlier by Drs.Richard Fahlman and Jack Tuszynski at the University of Alberta. In light of the differences in linker molecule lengths and attachment sites, computational modelling, particularly molecular docking simulations, has proven to be a valuable tool for exploring and comparing compounds to determine which ones preserve the binding activity to KRAS and E3.