Abstract

Angiogenesis, the formation of new capillary blood vessels from preexisting vasculature, is the process by which solid tumors are supplied with oxygen and nutrients1. Angiogenesis is increased in various types of cancers, and high microvessel density in the tumor correlates with poor prognosis in patients. Therefore, the inhibition of tumor angiogenesis is considered to be a promising approach for the treatment of many human malignancies2. The vascular endothelial growth factor (VEGF) family is a large family of angiogenic and lymphangiogenic growth factors, and VEGF plays an important role in tumor angiogenesis. Angiogenesis is triggered by the binding of VEGF to vascular endothelial growth factor receptor (VEGFR); the different subtypes of VEGFR include VEGFR1 (also known as Flt1), VEGFR2 (also known as KDR), and VEGFR3 (also known as Flt4)1,2. The VEGF receptor 2 (VEGFR2) is expressed on the surface of blood vessels, and it plays an important role in tumor angiogenesis. VEGF/VEGFR2 inhibition has been demonstrated as a cancer treatment method by using bevacizumab, a monoclonal antibody against VEGF, and several small molecule inhibitors of VEGFR2, such as sunitinib, axitinib, and pazopanib3. We studied the binding modes of 113 novel VEGFR2 kinase inhibitors using docking experiments and QSAR. We found that the orientations that these compounds adopt inside VEGFR2 binding site prioritize the effective interactions with Cys919, GLU885 and Asp1046, and the hydrophobic pocket, and we found too a model to explain the structure–activity relationship which predicted adequately the most active compounds contained in the test set. Furthermore, the analysis of the plots of the steric CoMSIA field describes the elements involved in the differential potency of the inhibitors that can be considered for the selection of suitable inhibitors.