M.Pharm Thesis 

Finding inhibitors that successfully target the non-small cell lung cancer (NSCLC) KRAS G12C mutation is crucial for the development of precision treatments. The objective of this computational study is to find possible KRAS G12C mutation inhibitors for non-small cell lung cancer (NSCLC). Swiss similarity and ADME analyses were used to select 17 compounds with beneficial pharmacokinetic characteristics. Ten ligands with strong binding conformations and affinities were found in a subsequent site-specific docking investigation, outperforming reference ligands. However, toxicology prediction classified all ligands as high-class III drugs, indicating the potential for anti-tumor actions while also justifying the requirement for Therapeutic Drug Monitoring (TDM) due to safety concerns. Future studies should focus on structurally improving compounds, empirically confirming their inhibitory action, and investigating combination therapy. Preclinical studies are necessary before conducting clinical trials in NSCLC patients carrying the KRAS G12C mutation to evaluate pharmacokinetics and effectiveness. The need of minimizing potential negative impacts should be highlighted. This study highlights the need for multidisciplinary approaches to improve NSCLC treatment results and offers significant insights for the creation of novel KRAS G12C inhibitors.

Keywords: KRAS G12C inhibitor; Virtual Screening; Adagrasib; Molecular Docking; Non-small cell lung cancer