Disentangling the nonbonding interaction energy between KRAS oncoproteins and small-molecule non-covalent inhibitors helps clarifying how inhibition occurs

Abstract Modeling small-molecule non-covalent inhibitors of RAS oncoproteins has so far been carried out at whole molecule level, thereby leaving important molecular details hidden. Actually, for the endless process of improving the inhibitor performance, a more detailed knowledge of such interactions is desirable. The challenge of improving on that situation has been taken here by disentangling the energies of interaction of KRAS G12D mutant residues with non-covalent inhibitors that, such as of BI-2865 or MRTX1133, are currently on the limelight. The problem was addressed to molecular dynamics and quantum mechanics-molecular mechanics computer simulations in the lack of suitable experimental approaches. It emerged where, at atomic detail, the inhibitor sticks better. In addition, for ternary complexes, such as of the non-covalent inhibitor RCM-6236 with cyclophilin A and KRAS, indications are provided as to the mechanism of inhibition. Such detailed views may offer clues as to where a new generation of inhibitors can stick even better to the receptor, and of repulsive situations to avoid.