Molecular screening of natural compounds targeting KRAS(G12C): a multi-parametric strategy against acute lymphoblastic leukemia.

Abstract

Acute lymphoblastic leukaemia (ALL) is a highly aggressive hematological malignancy that necessitates safer, more effective therapies. This study applied a multi-parametric computational approach to identify KRAS (G12C) inhibitors from African natural product databases. Six lead compounds (NA/EA-1 to NA/EA-6) were identified via virtual screening, molecular docking, and induced-fit docking, all showing stronger binding affinities (-14.50 to -10.53 kcal/mol) than the reference inhibitor Sotorasib (-8.34 kcal/mol). These candidates exhibited favorable pharmacokinetic and physicochemical properties, minimal Lipinski's rule violations, and non-toxic ADMET profiles. Four top hits were subjected to 200 ns molecular dynamics simulations, with NA/EA-3 demonstrating the greatest stability, lowest RMSD, and strongest hydrogen bonding. MM/GBSA analysis confirmed NA/EA-3 as the most promising compound (ΔG_total -54.42 kcal/mol), outperforming Sotorasib (-32.88 kcal/mol). These findings highlight NA/EA-3 as a potential KRAS(G12C) inhibitor for ALL therapy, warranting experimental validation.