Integrative NGSBased Genomic Profiling and StructureGuided Toxicity Prediction of KRAS G12C Inhibition

This study presents an integrated computational framework to investigate the structural, functional, and pharmacological aspects of KRAS G12C mutations in non–small-cell lung cancer (NSCLC). KRAS mutations, particularly the G12C variant, play a critical role in tumour progression and remain a major therapeutic challenge. In this work, sequence alignment and conserved domain analysis confirmed the evolutionary conservation and functional integrity of the KRAS protein. Structural comparisons revealed high similarity among available crystal structures, supporting their reliability for downstream modelling. Protein–protein interaction analysis highlighted KRAS as a central signalling hub interacting with key oncogenic pathways, including MAPK and PI3K signalling networks. Molecular docking studies demonstrated strong binding affinities of selected inhibitors, with trametinib showing the most favourable interaction, followed by adagrasib and garsorasib. Furthermore, in silico toxicity assessment indicated acceptable safety profiles for all compounds, with variations in predicted toxicity classes. Overall, the study provides a comprehensive bioinformatics and structure-based insight into KRAS G12C inhibition, emphasising its therapeutic relevance and supporting the development of targeted strategies in precision oncology.