Binding modes of the KRAS(G12C) inhibitors GDC-6036 and LY3537982 revealed by all atom molecular dynamics simulations

Almost 80 co-crystal structures of KRAS switch-II pocket (SII-P) targeting inhibitors are currently available in the RCSB Protein Data Bank. These publicly available structures are invaluable tools that have led to a more in-depth understanding of KRAS SII-P pocket, which is crucial for targeted drug design efforts. The binding modes (co-crystal structures) of two KRAS(G12C) inhibitors that have advanced to the clinical trials, GDC-6036 (divarasib) and LY3537982, are currently unavailable. Here, we reveal the putative binding modes of these two G12C inhibitors by utilizing the available structural data of analogous compounds and molecular dynamics (MD) simulations (total simulation time of 200 µs). Furthermore, we analyzed the energetical barrier related to their atropisomer interconversion by quantum mechanics (QM) calculations. Finally, biochemical assays supported our in silico observations, revealing remarkably high affinity for both inhibitors towards KRAS(G12C), which is, however, sacrificed by a co-mutation at Tyr96 (GDC-6036, LY3537982) or His95 (GDC-6036).