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

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.

Inhibiting the NLRP3 inflammasome with MCC950 ameliorates retinal neovascularization and leakage by reversing the IL-1β/IL-18 activation pattern in an oxygen-induced ischemic retinopathy mouse model

“…Previous studies have indicated that VEGF-A binds and activates receptor tyrosine kinase VEGFR2 on endothelial cells, triggering vascular growth and endothelial cell proliferation, migration, survival and increasing vascular permeability 27,[33][34][35] . The more VEGF molecules interact with VEGFR2, the stronger the promoting effect on blood vessels 36 .…”

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

“…In particular, the key interactions are three H-bonds (quinoline nitrogen and Cys 919 ; urea oxygen and Asp 1046 ; urea nitrogen and Glu 885 ), two hydrophilic interactions (the C-6 carboxamide with Asn 923 , bridged by water molecules) and several π-interactions (quinoline and C-4 phenoxy moiety with Leu 840 , Phe 818 and Lys 868 ) [ 130 ]. Quinoline core and urea moiety in tivozanib showed the same key interactions observed for the parent compound (PDB id: 4ASE) [ 131 , 132 ].…”

The Prowess of Andrographolide as a Natural Weapon in the War against Cancer

“…Molecular-docking module and biochemical analyses have shown that andrographolide acts as a highly efficient docking molecule that binds effectively to ATP-binding pocket of VEGFR2 and interferes with its kinase activity [45].…”