Molecular docking and dynamics analysis of selected phytocompounds against multi-targeted hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related deaths worldwide, with a five-year survival rate of only 19%. Although Sorafenib is the primary systemic therapy, its limited efficacy and complex interactions with signaling pathways highlight the need for multi-target drugs.

This study evaluates the anti-cancer properties of selected phytochemicals against six key HCC target proteins, utilizing sorafenib tosylate as a positive control. Molecular docking was performed to evaluate binding affinities and interactions, and ADME/T predictions were generated to estimate drug-like properties. The top-ranking candidates were further evaluated using 100-ns molecular dynamics simulations to analyze conformational stability, protein-ligand interactions, and residue mobility.

Silymarin (SA) emerged as the most effective compound, demonstrating greater predicted inhibitory activity than Sorafenib. SA showed high binding affinity for target proteins 6HH1 (-9.9 kcal/mol) and 1CM8 (-9.6 kcal/mol). Molecular dynamics simulations also revealed increased stability of the SA-protein complexes, particularly for the 1CM8-SA complex, which maintained high conformational stability. The root-mean-square deviation (RMSD) value was found to be around 2.1 Å, and the root-mean-square fluctuation (RMSF) values were below 3 Å, indicating lower protein flexibility compared to both the native and sorafenib-bound complexes.

These computational findings provide a strong theoretical basis for Silymarin's efficacy as a highly potent, multi-targeted therapeutic agent against HCC. The improved stability and binding properties of Silymarin compared with Sorafenib provide a strong rationale for advancing this compound into preclinical and clinical studies.