Next Generation Sequencing (NGS) and Artificial Intelligence for structural and Functional Analysis of KRAS G12C in Complex with Novel Inhibitors

Lung cancer is still one of the most dangerous cancers in the world, and non-small cell lung cancer (NSCLC) is the most dominant subtype. Among many genetic drivers of NSCLC, the KRAS-G12C mutation is an important one that drives uncontrolled cell growth through sustained activation of MAPK and PI3K/AKT signaling pathways. Nevertheless, inhibition of KRAS mutations has for a long time been elusive because of the high binding affinity of KRAS to GTP and the lack of proper binding sites. New developments in Next-Generation Sequencing (NGS) and Artificial Intelligence (AI) provide exciting prospects for the elucidation and targeting of KRAS-mediated oncogenesis.This research is centered on the integrative analysis of KRAS-G12C with the use of advanced computational approaches. We utilized NGS to identify KRAS-G12C mutations in patient samples and inspected genomic changes using sequence scanning programs like InterProScan. Structural analysis was conducted at high resolution molecular visualization, creating detailed protein-ligand interaction and structural motif visualization, including helices, sheets, and loops. Molecular docking simulations confirmed the engagement of KRAS-G12C with the in-cancer-targeted inhibitor JAB-16 (PDB ID: 9KPM) exhibiting excellent structural resemblance (RMSD scores 0.411 and 0.598) to homologous protein models.AI-based methods, such as AlphaFold for predicting structures and deep learning algorithms for molecular dynamics simulations, were employed to simulate conformational changes and interaction dynamics. Embedding analyses (t-SNE plots, hierarchical clustering, and heatmaps) identified significant biochemical patterns, including conserved functional domains like the G1 P-loop and switch regions important for GTP binding and hydrolysis. Structural validation by ERRAT confirmed high-quality predicted protein models.The results underscore the strength of combining NGS and AI technologies to improve precision oncology through better structural knowledge of KRAS-G12C and drug discovery. This strategy opens up avenues for designing noninvasive imaging probes as well as targeted therapy against KRAS-mutant lung cancer.