Computational investigation of ascorbic acid as an anticancer drug: Electronic structure, molecular docking, and molecular dynamics study

The high mortality associated with colorectal cancer highlights the need for protective and therapeutic agents that can improve treatment outcomes. The notable side effects linked to conventional treatments make the exploration of naturally occurring compounds, such as ascorbic acid (AA), not only appealing but essential. Although initial in vitro studies have demonstrated AA’s anticancer properties, the specific molecular mechanisms governing its interactions with key colorectal cancer-related proteins remain poorly understood. Furthermore, there is a lack of comprehensive computational studies that combine electronic structure analysis with dynamic binding behaviors. This work builds upon our previously published experimental findings demonstrating AA-induced apoptosis and Caspase-3 activation in Caco-2 colorectal cancer cells. Herein, we investigate the electronic structure of AA and its binding affinity to four proteins associated with colorectal cancer (CRC): Caspase-3, BCL-2, CDK2, and p53. The electronic structure was analyzed using DFT calculations, incorporating molecular electrostatic potential (MEP), Non-Covalent Interactions (NCI) analysis, topological analysis, and Hirshfeld surface analysis. Molecular docking revealed favorable predicted binding of AA to the proteins through hydrogen bonding and van der Waals interactions, with the highest affinity observed for Caspase-3, consistent with our experimental results. Co-docking AA with doxorubicin improved the predicted binding affinity, suggesting a potential cooperative binding effect. Furthermore, molecular dynamics simulations indicated good stability of AA within the active pocket of Caspase-3. Binding energy calculations using the g_mmpbsa method showed that AA exhibited a binding energy of –13.745 kJ/mol, closely matching that of the native co-crystallized ligand (–14.217 kJ/mol).