aMulti-target in silico profiling of silymarin derivatives against oncogenic pathways: Integration of docking, DFT,...

Silymarin derivatives, renowned for their antioxidant and hepatoprotective properties, have recently emerged as promising candidates for anticancer therapy due to their potential to modulate critical oncogenic pathways. Four silymarin derivatives (silibinin, isosilibinin, silicristin, silidianin), known for liver protection, were explored as potential multi-target anticancer agents using computational methods. Molecular docking against key cancer proteins (AKT, PI3K, PARP, mTOR, GSK3-β, PDK1, PAK4) identified silicristin as the strongest binder, confirmed by stable molecular dynamics simulations and favorable binding energy (ΔG = -125.78 kcal/mol via MM-GBSA). Silidianin showed the highest chemical reactivity (smallest HOMO-LUMO gap: 0.1535 eV). All compounds displayed promising ADMET profiles: high intestinal absorption, low blood-brain barrier penetration, and silidianin exhibited the lowest acute toxicity (LD₅₀ = 10,000 mg/kg). While potential immunotoxicity was noted, silicristin and silidianin emerged as the most promising candidates due to their strong target binding, stability, reactivity, and favorable safety predictions, warranting further experimental validation. This multi-scale computational study identifies silicristin and silidianin as promising multi-target anticancer candidates. Their stability, favorable electronic profiles, and low predicted toxicity support further in vitro and in vivo validation.