Natural Alkaloids as Promising Candidates for Targeted Therapy in Lung Cancer

The KRAS oncogene (EC 3.6.5.2) is the most frequently mutated gene in non-small cell lung cancer (NSCLC), being present in approximately 25–30% of cases. Among these alterations, the KRAS p.G12C mutation is particularly relevant, occurring in ~12–14% of NSCLC and strongly associated with smoking. This mutation impairs GTP hydrolysis and promotes constitutive activation of the protein, driving uncontrolled cell proliferation. Tumors harboring this mutation usually show poor response to EGFR-targeted therapies, although they may benefit from immunotherapy. More recently, covalent inhibitors have shown clinical efficacy by specifically targeting KRAS G12C; however, both primary and acquired resistance remain significant challenges, highlighting the need for novel therapeutic strategies. In this context, a library of 249 alkaloids was constructed and subjected to virtual screening against the oncogenic KRAS G12C variant (PDB: 4NMM, Homo sapiens). Following the docking studies, their toxicity and pharmacokinetic properties were predicted in silico using the StopTox platform. Protein preparation included validation of the docking protocol through re-docking of the co-crystallized ligand, 5'-O-[(S)-{[(S)-2-(acetylamino)ethoxyphosphoryl]oxy}(hydroxy)phosphoryl]guanosine. Docking simulations were performed in YASARA using the AutoDock Vina engine. The results identified four alkaloids with binding energies superior to the crystallographic control (-8.40 kcal/mol): Oxoisocoridine (-8.99 kcal/mol), Aporglauquine (-8.67 kcal/mol), Oxyaporphine (-8.60 kcal/mol), and Oxyisocoridine (-8.45 kcal/mol). Toxicity predictions indicated that all candidates are non-toxic orally, non-irritant to the eyes, non-sensitizing, and non-corrosive to the skin, according to computational models. Overall, these findings suggest that alkaloids represent promising scaffolds for KRAS G12C inhibition, combining high predicted binding affinities with a favorable toxicity profile. Nonetheless, experimental validation is essential to confirm their potential as anticancer candidates.