Molecular docking analysis reveals differential binding affinities of multiple classes of selective inhibitors towards cancer-associated KRAS mutants

Abstract

KRAS is the most frequently mutated oncogene in solid cancers, and inhibitors that specifically target the KRAS-G12C mutant were recently approved for clinical use. The limited availability of experimental data pertaining to the sensitivity of KRAS-non-G12C mutants towards RAS inhibitors made it difficult to predict the response of KRAS-mutated cancers towards RAS-targeted therapies. The current study aims at evaluating sensitivity profiles of KRAS-non-G12C mutations towards clinically approved sotorasib and adagrasib, and experimental RAS inhibitors based on binding energies derived through molecular docking analysis. Computationally predicted sensitivities of KRAS mutants conformed with the available but limited experimental data, thus validating the usefulness of molecular docking approach in predicting clinical response towards RAS inhibitor treatment. Our results indicate differential sensitivity of KRAS mutants towards both clinical and experimental therapeutics; while certain mutants exhibited broad cross-resistance to most inhibitors, some mutants showed resistance towards specific inhibitors. These results thus suggest the potential of emergence of more resistance mutations in future towards RAS-targeted therapy and points to an urgent need to develop novel classes of inhibitors that are able to overcome both primary and secondary drug resistance.

Supplementary information: The online version contains supplementary material available at 10.1007/s13205-022-03407-9.

Keywords: Adagrasib; Drug sensitivity; KRAS protein; Non-G12C mutations; RAS inhibitors; Sotorasib.

Fig. 1

Binding affinities of wildtype and KRAS-G12X mutants towards GTP, sotorasib and adagrasib. a Chemical structures of GTP and clinically approved covalent inhibitors (sotorasib and adagrasib) of KRAS b Drug binding affinities shown in terms of percentage binding affinity as compared to G12C (100%) as reference

Fig. 2

Molecular Dynamic simulations of G12S and G12A mutants. RMSD plots for backbone cα atoms relative to their initial minimized complex structure as a function of time a G12C/A/S mutants in complex with sotorasib b G12C/A/S mutants in complex with adagrasib. RMSF plot for cα atoms relative to their initial minimized complex structure as a function of the amino acid residues in the structure: c G12C/A/S mutant-sotorasib complexes d G12C/A/S mutant-adagrasib complexes. Interaction energies of KRAS mutants G12C/A/S were depicted towards sotorasib e and adagrasib f

Fig. 3

Binding affinities of KRAS-non-G12X mutants towards GTP, sotorasib and adagrasib. a Multiple sequence alignment of RAS isoforms; KRAS mutants taken in the study are highlighted in blue and red. b Drug binding affinities measured in terms of percentage binding affinity as compared to G12C (100%) mutant. SW1: Switch-I region, SW2: Switch-II region, HVR: Hypervariable region

Fig. 4

Binding affinities of KRAS-non-G12C mutants towards eight additional inhibitors a Chemical structures of RAS inhibitors b Drug sensitivity profiles of KRAS-G12X and KRAS-non-G12X mutants towards eight experimental RAS inhibitors