Title:In Silico Docking Studies of Vascular Endothelial Growth Factor-A (VEGFA): Possible Implications in Chronic Myeloid Leukemia (CML) Therapy
Volume: 18
Issue: 4
Author(s): Samyuktha Lakkireddy, Archana Jayaraman, Sangeetha Aula, Atya Kapley, Vijay Kumar Kutala and Kaiser Jamil*
Affiliation:
- Centre for Biotechnology and Bioinformatics, School of Life Sciences, Jawaharlal Nehru Institute of Advanced Studies (JNIAS), Kimtee Enclave, Banjara Hills, Hyderabad, Telangana-500034,India
Keywords:
Angiogenesis, VEGFA expression, chronic myeloid leukemia, natural anti-VEGFA inhibitors, tyrosine kinase
inhibitors, stem cell.
Abstract:
Background: Dysregulated angiogenesis resulting in neovascularization is a critical
event in the expansion and progression of Chronic Myeloid Leukemia (CML), 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
was: 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.
