Design, synthesis, and docking studies of peptidomimetics based on HER2-herceptin binding site with potential antiproliferative activity against breast cancer cell lines.
Design, synthesis, and docking studies of peptidomimetics based on HER2-herceptin binding site with potential antiproliferative activity against breast cancer cell lines.
复制标题
DOI：
10.1111/j.1747-0285.2009.00855.x
复制
发表时间：
2009-09
影响因子：
3
通讯作者：
Lin GM
中科院分区：
文献类型：
--
作者：
Satyanarayanajois S;Villalba S;Jianchao L;Lin GM
表皮生长因子受体（EGFR）激酶和相关的人表皮生长因子受体-2 （HER2, ErbB2）是两种与癌症有关的生长因子受体。HER2的过表达或活化在乳腺癌、卵巢癌和肺癌中经常发生，使其成为治疗癌症的重要靶点。用抗体或小分子阻断her2介导的信号传导已被证明可有效抑制细胞生长。在分析了HER2-herceptin复合物的晶体结构后，设计了几种肽模拟物（HERP5, 6和7）来抑制her2介导的细胞生长信号。我们使用了一种硅筛选方法来研究所设计化合物的化学多样性。利用Autodock软件将HERP5和HERP7的不同类似物与HER2蛋白胞外结构域对接。共有53个化合物与HER2蛋白对接，并从对接能量、氢键和疏水相互作用等方面分析了它们的结合模式。具有低能对接结构的化合物被选择用于化学合成和生物活性。其中两种化合物（HERP5和HERP7）对过表达HER2蛋白的SKBR-3细胞株（乳腺癌细胞株）表现出抗增殖活性，IC50值分别为0.396 μM和0.143 μM。
Epidermal growth factor receptor (EGFR) kinase and the related human epidermal growth factor receptor-2 (HER2, ErbB2) are two growth factor receptors that have implications in cancer. The overexpression or activation of HER2 occurs frequently in breast, ovarian, and lung cancers, making it an important therapeutic target in the treatment of cancer. Blocking HER2-mediated signaling with antibodies or small molecules has been shown to be effective in inhibiting cell growth. After analyzing the crystal structure of the HER2-herceptin complex, several peptidomimetics (HERP5, 6 & 7) were designed to inhibit HER2-mediated signaling for cell growth. We have used an in silico screening method to investigate the chemical diversity of the designed compounds. Autodock software was used to dock the different analogs of HERP5 and HERP7 with HER2 protein extracellular domain. A total of 53 compounds were docked to HER2 protein, and their binding modes were analyzed in terms of docking energy, hydrogen bonding, and hydrophobic interactions. Compounds that exhibited low energy docked structures were chosen for chemical synthesis and biological activity. Two of the compounds (HERP5 and HERP7) exhibited antiproliferative activity, with IC50 values of 0.396 μM and 0.143 μM, respectively, against SKBR-3 cell lines (breast cancer cell lines) that overexpress HER2 protein.
登录
查看更多内容
影响因子：
45.3
作者：
Cobleigh, MA;Vogel, CL;Slamon, DJ
通讯作者：
Slamon, DJ
影响因子：
50.3
作者：
Agus, DB;Akita, RW;Sliwkowski, MX
通讯作者：
Sliwkowski, MX
影响因子：
64.8
作者：
Cho, HS;Mason, K;Leahy, DJ
通讯作者：
Leahy, DJ
影响因子：
5.8
作者：
Pérez-Soler, R
通讯作者：
Pérez-Soler, R
影响因子：
11.2
作者：
Rabindran, SK;Discafani, CM;Wissner, A
通讯作者：
Wissner, A