Ebadi Ahmad, Razzaghi-Asl Nima, Shahabipour Sara, Miri Ramin
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 .
Department of Medicinal Chemistry, School of Pharmacy, Ardabil University of Medical Sciences.
Iran J Pharm Res. 2014 Spring;13(2):405-15.
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.
血管内皮生长因子受体-2（VEGFR-2）；作为血管内皮生长因子的一种细胞表面受体，是参与细胞增殖/血管生成的关键药理学靶点。研究表明，VEGFR-2通过激活细胞外信号调节激酶途径诱导细胞增殖。因此，靶向VEGFR-2被认为是开发抗肿瘤药物的有效途径。莫特沙尼是VEGFR-1、2和3的小分子拮抗剂（IC50分别为2 nM、3 nM、6 nM）。它是一种正在进行针对某些类型癌症临床试验的候选实验药物。在本研究中，对莫特沙尼（AMG 706）与VEGFR-2活性位点的单个氨基酸的结合能进行了评估（氨基酸分解分析）。为此，使用了与采用极化函数的分裂价基组（Def2-SVP）相关的泛函B3LYP。对配体在优化状态和晶体状态下的构象进行比较分析表明，莫特沙尼在其最低能量构象中不一定与VEGFR-2活性位点结合。
