Computational Modeling of Clinically Approved Alkylating Agents Against Epidermal and Fibroblast Growth Factor Receptors: A Step Toward Liver Cancer Therapeutics

Abstract

Cancer is a leading cause of death, which occurs due to various factors like mutations, radiation, and many other factors. Still, no benefit has been established worldwide. To overcome this problem, the current study aimed to evaluate the anti-hepatocellular carcinoma and anti-hepatoblastoma potential of commonly used drugs against a specific type of cancer. The five most active alkylating agents, including melphalan (hepatocarcinoma), mitomycin C (anticancer and antibiotic), estramustine (prostate cancer), pipobroman (leukemia), and irofulven (prostate cancer), were selected for in silico molecular docking. The given agents were downloaded from PubChem with CID 460612, 5746, 259331, 4842, and 148189, respectively. The protein targets epidermal growth factor (HER2) and fibroblast growth factor were retrieved from the Protein Data Bank with PDB IDs 1N8Z and 6NVG. The target and ligands were optimized or prepared to perform virtual screening and toxicity studies. The physicochemical, lipophilicity, water solubility, pharmacokinetics, and drug likeness were analyzed. The molecular docking results showed that estramustine exhibited greater inhibition against HER2 and fibroblast growth factor, with binding energies of -7.9 and -7.7 Kcal/mol, respectively, compared to other alkylating agents. But other agents also exhibited inhibitory potential against the HER2 and fibroblast growth factor, using strong hydrogen bonding with reasonable binding energies. The computational approach reflects that the specific targeted anticancer agents attenuate the activities of the selected targets by inhibiting the major signaling pathways, such as angiogenesis and cancer cell proliferation. The finding suggested that the specifically targeted drugs could be used against hepatocarcinoma or hepatoblastoma.