Molecular Docking and In-Silico Toxicity Analysis of Classical Alkylating Agents Against VEGF: Uncovering the Anti-Angiogenic Potential

Abstract

This study explored the novel anti-angiogenic effect of the classical alkylating agents using their ability to directly interact with Vascular Endothelial Growth Factor (VEGF), the key controller of tumor angiogenesis and resistance to combinations of chemotherapy. The alkylating agents commonly used in clinical practice, namely, Mitomycin C, Melphalan, Chlorambucil, and Cyclophosphamide, were evaluated with the assistance of the molecular docking program, AutoDock Vina, integrated within YASARA, for the structural visualization and interaction profiling. Mitomycin C showed the highest binding affinity to VEGF (−7.4 kcal/mol) as it exhibited large-scale interaction with key residues of the cystine-knot motif mediating VEGF binding to VEGFR, which implies the possibility of inhibiting the interaction with the receptor. Melphalan, Chlorambucil and Cyclophosphamide showed moderate binding via hydrophobic and aromatic interactions inside the VEGF functional cleft, and Cyclophosphamide weak peripheral interactions. These results reveal that some alkylating agents might have direct anti-angiogenic actions beyond their known DNA-damaging processes that explain clinical findings of vascular inhibition on treatment. Furthermore, In-silico toxicity study also confirmed the mutagenic, carcinogenic, and organ-targeted toxicities of selected alkylating agents. Moreover, ADME profiling also showed specific absorption, permeability, and metabolic behaviors, which are associated with pharmacological activity. Together, these studies highlight Mitomycin C as a promising dual-mechanism candidate, which can both destroy tumor DNA and regulate angiogenesis by binding the VEGF. These findings support the use of alkylating chemotherapeutics as economical anti-angiogenic agents and provides a basis to the design and experimental validation of hybrid drugs which combine cytotoxic and anti-vascular action.