In silico study of Sobuzoxane for VEGF-B mediated lymphangiogenesis targeting triple negative breast cancer

Radiation resistance is a major limitation in breast cancer therapy, although the chemotherapeutic drugs are well regarded for its efficiency in targeting rapidly proliferating cancer cells. Molecule such as 9-amino camptothecin was explored as radiosensitizer to address this concern of resistance. Pharmacophore modelling was used in this study to modify the structure of this molecule to get a derivative named Sobuzoxane which showed promising radiosensitizing activity and ability of mimic OH-lactone ester. In triple negative breast cancer, VEGF-B is known for vascular remodeling and madulating endothelial survival. Hence, it indirectly supports the tumour proliferation. Therefore, ligands were optimized to increase the VEGF-B targeting ability by refining hydrogen bond donors, acceptors, hydrophobic interactions, and aromatic features. The selected hit was further used for molecular docking, MD simulation and ADMET analysis. It was found that Subuzoxane has higher binding affinity towards VEGF-B compared to the 9-amino camptothecin, hence could minimize the protein destabilization. Number of hydrogen bonds between VEGF-B-Sobuzoxane complex could further be increased by the incorporation of a neutralizing antibody Fab fragment. This indicates greater stability and specificity within the complex. Structural stability and persistence of protein-ligand complex were analysed by molecular dynamic simulation study for 100 ns. The stable binding was evident by the persistent interaction profile visualized throughout the MD simulation. Moreover, strong ligand-protein interaction potential along with good solubility was established by ADME analysis. In-silico analysis conducted in this study recognised Sobuzoxane as a potential radiosensitizer targeting VEGF-B for angiogenesis-mediated triple negative breast cancer. Finally, this study provides new understanding about the increased stability of Subuzoxane-VEGF-B complex in presence of a neutralizing antibody Fab fragment as a result of enhanced hydrogen bonding.