Identification of Potent VEGF Inhibitors for the Clinical Treatment of Glioblastoma, A Virtual Screening Approach

Mohini Yadav,Sivaraj Srinitha,Ravina Khandelwal,Natasha Khandekar,Anuraj Nayarisseri,Urvy Mudgal,Sugunakar Vuree,Sanjeev Kumar Singh

doi:10.31557/apjcp.2019.20.9.2681

Abstract

Vascular endothelial growth factor (VEGF) expression could be found in all glioblastomas. VEGF takes part in numerous changes including the endothelial cell proliferation, the vasculature of solid tumor: its survival invasion, and migration, chemotaxis of bone marrow-derived progenitor cells, vasodilation and vascular permeability. VEGF inhibition can be a smart therapeutic strategy because it is extremely specific and less toxic than cytotoxic therapy. To establish better inhibition of VEGF than the current inhibitors, present study approach is by molecular docking, virtual screening to illustrate the inhibitor with superior affinity against VEGF to have a cautious pharma profile. To retrieve the best established and high-affinity high affinity molecule, Molegro Virtual Docker software was executed. The high-affinity scoring compounds were subjected to further similarity search to retrieve the drugs with similar properties from pubchem database. The completion of virtual screening reveals that PubChem compound SCHEMBL1250485 (PubChem CID: 66965667) has the highest affinity. The study of the drug-likeness was verified using OSIRIS Property Explorer software which supported the virtual screened result. Further ADMET study and drug comparative study strongly prove the superiority of the new established inhibitor with lesser rerank score and toxicity. Overall, the new inhibitor has higher potential to stop the expression of VEGF in glioblastoma and positively can be further analysed through In vitro studies.

Highlights

The term ‘glioma’ comprehends all tumors encompassing the glial cell origin, including astrocytoma grades I, II, III and IV (Schwartzbaum et al, 2006)
To establish better inhibition of Vascular endothelial growth factor (VEGF) than the current inhibitors, present study approach is by molecular docking, virtual screening to illustrate the inhibitor with superior affinity against VEGF to have a cautious pharma profile
We proposed a newly screened inhibitor which directly can block the active site of VEGFR and have found to be less toxicity and cytotoxicity on ADMET analysis

Summary

Introduction

The term ‘glioma’ comprehends all tumors encompassing the glial cell origin, including astrocytoma grades I, II, III and IV (Schwartzbaum et al, 2006). Grade 4 which is Glioblastoma multiforme (GBM), is the most aggressive and the most common in humans This brain tumor drew the noteworthy attention of scientists and doctors all over the world as patients with GBM die within a year having no scope of long term survival. GBM is excessively showing regions of necrosis and haemorrhage (Holland, 2000) This lethal GBM reappears in most patients and no effective generalized treatment exists for the recurrent diseases up till now. A case study of 153 recurrent glioblastoma patients in 2014 summarises the approval by the FDA on the most effective drug bevacizumab, which can increase the survival up tomonths, which 38% and combined treatment of bevacizumab with lomustine can increase the survival rate up to 59%.

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