New insights into the anti-hepatoma mechanism of Alisol G-metal ions complexes based on c-myc DNA

This study investigated the anti-hepatoma molecular mechanism of Alisol G, which is an effective component of the Chinese medicine Alisma orientalis, in the presence of metal ions Cu2+ and Fe3+ based on c-myc DNA. Here, a combination of Alisol G and metal ions (Cu2+, Fe3+) to augment anti-hepatoma efficiencies of Alisol G has been identified by methyl thiazolyl tetrazolium (MTT) assay. Network pharmacology revealed that c-myc DNA was the potential target of Alisol G with respect to its anti-hepatoma effects. By performing multi-spectroscopic analyses, we showed that the interaction of Alisol G with c-myc DNA was a process of static quenching. The binding constants and thermodynamic constants indicated that a 1:1 complex was formed between Alisol G and c-myc DNA. Moreover, metal ions strengthened the interaction between Alisol G and c-myc DNA. Molecular docking and molecular dynamics simulation further unveiled that the higher binding affinity between Alisol G-Fe3+ complex and c-myc DNA as compared to Alisol G-Cu2+ complex. This probably resulted from the polarization of metal ions and the structural flexion of Alisol G. The C22-O31-H76 and C18-O32-H77 of Alisol G were key groups in the interaction with c-myc DNA. Addition of metal ion, had greatly changed the c-myc DNA-binding domain of Alisol G while didn’t affect the kinetic stability of the interaction, thus facilitating the insertion of Alisol G into c-myc DNA A-T base pair. Importantly, the DG113 of c-myc DNA was important for its binding to metal ions. Together, our findings suggested that Alisol G in combination with metal ions may be an efficient and promising option for the treatment of liver cancer.