Dynamic geometric constraints govern covalent feasibility in KRAS G12C ligands

Abstract Covalent inhibition has emerged as an effective strategy for targeting oncogenic proteins, yet successful covalent engagement depends not only on binding affinity but also on the dynamic preservation of productive electrophile–thiol geometry [1,2]. Motivated by the clinical success of acrylamide-based KRAS G12C inhibitors such as sotorasib, we performed a structure-based and molecular dynamics investigation of acrylamide-containing KRAS G12C ligands. Although several ligands initially achieved near-reactive proximity to Cys12, production molecular dynamics simulations revealed rapid relaxation of the pre-reactive geometry and loss of productive electrophile–thiol alignment. Similar geometric relaxation was observed for noncovalent sotorasib simulations, whereas covalent KRAS G12C complexes preserved stable sulfur–carbon distances and chemically consistent bond geometries throughout explicit-solvent molecular dynamics. These findings suggest that covalent feasibility in KRAS G12C is governed by stringent dynamic geometric constraints and emphasize the importance of reactive-state preorganization in covalent inhibitor design.