Andrographolide binds to ATP-binding pocket of VEGFR2 to impede VEGFA-mediated tumor-angiogenesis

Kirti Kajal,Pushpak Bhattacharjee,Sayantan Bose,Jyotsna Bhat,Santosh K Kar,Tania Sarkar,Dwaipayan Chakraborty,Abir K Panda,Subhrangsu Chatterjee,Gaurisankar Sa

doi:10.1038/s41598-019-40626-2

Kirti Kajal, Pushpak Bhattacharjee + Show 8 more

Open Access

https://doi.org/10.1038/s41598-019-40626-2

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Journal: Scientific Reports	Publication Date: Mar 11, 2019
Citations: 24	License type: open-access

Affiliation: Bose Institute

Abstract

Vasculogenesis and angiogenesis are process of formation of blood vessels. Blood vessels are evolved to distribute nutrients and oxygen to distant organs. These vessels are crucial for growth and repair of wounded tissue. During tumor condition there occurs imbalance in the growth of blood vessels which leads to neo-angiogenesis. Neo-angiogenesis is major perpetrator behind the establishment of tumor. Tumor cells secrete pro-angiogenic factor VEGFA which binds to VEGFR2 present over surface of endothelial cells and triggers formation of new blood vessels. To inhibit tumor-angiogenesis, a physiologically-safe small molecule inhibitor was screened which can potentially interact with kinase domain of VEGFR2 and inhibit its activity. Molecular-docking module and biochemical analysis identified andrographolide as one of the best docking molecules that binds to ATP-binding pocket of VEGFR2 and inhibits its kinase activity. Thus, for a more radical approach towards safe VEGFR2 inhibitor, andrographolide was repurposed to inhibit tumor-angiogenesis and reduce tumor burden.

Highlights

After an era of intense research, cancer is still a major area of concern
vascular endothelial growth factor (VEGFA) secreted by tumor cells, bind to VEGFR2 and promote neo-vascularization
To inhibit the neo-angiogenesis we searched for a small molecule inhibitor which can potentially interact with the VEGFR2 kinase domain and inhibits its activity

Summary

Introduction

After an era of intense research, cancer is still a major area of concern. It has the capacity to survive in all conditions and paralyze host system[1]. A preliminary search indicates that the well-known small molecule, andrographolide, binds to the kinase domain of VEGFR2 and inhibits its kinase activity. VEGFA secreted by tumor cells, bind to VEGFR2 and promote neo-vascularization. To inhibit the neo-angiogenesis we searched for a small molecule inhibitor which can potentially interact with the VEGFR2 kinase domain and inhibits its activity.

Results

Conclusion