Ab-initio and conformational analysis of a potent vegfr-2 inhibitor: a case study on motesanib

Vascular endothelial growth factor receptor-2 [VEGFR-2]; a cell surface receptor for vascular endothelial growth factors, is a key pharmacological target involved in the cell proliferation/angiogenesis. It has been revealed that VEGFR-2 induces proliferation through activation of the extracellular signal-regulated kinases pathway. In this regard, targeting the VEGFR-2 has been considered as an efficient route to develop anti-tumor agents. Motesanib is a small-molecule antagonist of VEGFR-1, 2, and 3 [IC50s; 2 nM, 3 nM, 6 nM, respectively]. It is an experimental drug candidate undergoing clinical trials against some types of cancer. In the present study, Motesanib [AMG 706] was evaluated in terms of its binding energies with individual amino acids of VEGFR-2 active site [amino acid decomposition analysis]. For this purpose, functional B3LYP associated with split valence basis set using polarization functions [Def2-SVP] was used. Comparative Conformational analysis of the ligand in optimized and crystallographic states revealed that Motesanib does not necessarily bind to the VEGFR-2 active site in its minimum energy conformer