Design and evaluation of KRAS-targeting heteroaromatic thiosemicarbazone scaffolds for lung cancer: an integrated molecular docking, DFT calculations, and preclinical study

This study aimed to develop a novel KRAS-targeting scaffold for non-small cell lung cancer (NSCLC) treatment by synthesizing and evaluating a heteroaromatic thiosemicarbazone compound (Htc). We hypothesized that the unique structural features of thiosemicarbazones would enable effective binding to the KRAS G12C mutant protein. The compound was synthesized via template methodology and characterized through elemental analysis, FT-IR, NMR, and SEM-EDS. In vitro cytotoxicity against H460 NSCLC cells revealed significant antiproliferative activity. Molecular docking with KRAS G12C (PDB: 5YXZ) showed the most favorable conformation, which showed a docking score of -7.52 kcal/mol, corresponding to an approximate inhibition constant (Ki) of 3.08 µM. DFT calculations (B3LYP/6-311 + + G(d, p)) revealed a HOMO-LUMO gap of 2.182 eV, indicating molecular stability and reactivity suitable for biological interactions. These findings suggest that our heteroaromatic thiosemicarbazone represents a promising scaffold for the development of targeted KRAS G12C ligands for lung cancer therapy.