title: Ab-initio and Conformational Analysis of a Potent VEGFR-2 Inhibitor: A Case Study on Motesanib.
abstract: 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.
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. ; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran .
authors.forename: Ahmad
authors.initials: A
authors.lastname: Ebadi
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences.
authors.forename: Nima
authors.initials: N
authors.lastname: Razzaghi-Asl
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
authors.forename: Sara
authors.initials: S
authors.lastname: Shahabipour
authors.affiliation: Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. ; Department of Medicinal Chemistry, School of Pharmacy, Shiraz University of Medical Sciences, Shiraz, Iran .
authors.forename: Ramin
authors.initials: R
authors.lastname: Miri
keywords: B3LYP; Cancer; DFT; Motesanib; VEGFR-2