Background: Dysregulated angiogenesis resulting in neovascularization is a critical event in the expansion and progression of
Chronic Myeloid Leukemia (CML), a hematopoietic cancer. Vascular Endothelial Growth Factor- A (VEGFA), an important angiogenesis
mediator, has been a target for treating cancer. Although several anti-VEGFA drugs are available, they are associated with adverse side effects,
promoting the need to identify better drugs that may be less toxic.
Objective: Our aim was to investigate whether Tyrosine Kinase Inhibitors (TKIs) could be repurposed for use as VEGFA inhibitors via in
silico docking software. We also investigated the potential of phytochemicals as VEGFA inhibitors.
Methods: We performed molecular docking using Schrödinger Maestro software suite 2014-3 to determine the most potent phytochemical
and TKI VEGFA antagonists.
Results: Among the TKIs investigated, Bosutinib had the best binding affinity and may be the most potent TKI against VEGFA. The order
of binding affinities for the top ten docked ligands were: Ginsenoside Rg3> Bosutinib> Vitamin D> Paclitaxel> Dasatinib> Saponins>
Ponatinib> Squalamine> Imatinib> Nilotinib. We found that Ginsenoside Rg3 had the highest binding affinity (MMGBSA score= -99.4
kcal/mol, glide Gscore = -9.16 kcal/mol) to VEGFA.
Conclusion: Our study has shown for the first time the binding poses of these TKIs and phytochemicals to VEGFA, using computational
methods. We propose that the use of the top scoring ligands, in isolation or a combination of phytochemicals plus TKI, could serve as potent
angiogenesis inhibitors via their binding to and inhibiting VEGFA expression to prevent CML progression. We have also profiled the
ligand binding residues which may be explored in designing pharmacophores.