Computational assessment of the binding modes of the first VHL-recruiting PROTACs designed for oncogenic KRasG12C

Abstract

A computational investigation was employed to better understand the engagement mechanism for the formation of ternary complexes involving VHL-recruiting PROTACs designed for oncogenic KRas^G12C. Rounds of protein–protein docking followed by conformational searches enabled the prediction of the most likely ternary complexes for each PROTAC, which were further validated through rounds of MD simulations. The methodology was applied to six PROTAC molecules (LC1–LC6) that were previously designed, synthesized, tested in cell assays, and reported in the literature. These control systems included five different linker sizes and were derived from the KRas^G12C covalent ligand MRTX849 and the VHL ligand 3. Our results suggest that these compounds are capable of engaging KRas^G12C and VHL, forming dynamically stable ternary complexes under a predominant binding mode. It was also observed that KRas^G12C and VHL exhibit similar dynamic behaviors for binding the PROTAC versus the individual ligand warheads with no linker. Our findings reinforce the concept that this methodology can serve as a powerful tool for designing structures and prioritizing compounds for further synthesis and biological evaluation.