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GRP78-targeted in-silico virtual screening of novel anticancer agents.
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-05-31 , DOI: 10.1111/cbdd.13322 Ambily Nath Indu Viswanath 1, 2 , Ji Woong Lim 1, 3 , Seon Hee Seo 1 , Jae Yeol Lee 3 , Sang Min Lim 1 , Ae Nim Pae 1, 2, 3
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2018-05-31 , DOI: 10.1111/cbdd.13322 Ambily Nath Indu Viswanath 1, 2 , Ji Woong Lim 1, 3 , Seon Hee Seo 1 , Jae Yeol Lee 3 , Sang Min Lim 1 , Ae Nim Pae 1, 2, 3
Affiliation
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Overexpression of GRP78 in a variety of cancers such as glioblastoma, leukemia, lung, prostate, breast, gastric, and colon makes it a prime target for anticancer drug development. Present study reports GRP78-based design of novel anticancer agents using in-silico methods. As a first step toward the work, the interactions between GRP78 and 15 known ligands were modeled by docking simulation. The docked complex, GRP78-13, superior to other compounds with respect to its experimental activity and energy descriptors, was deduced into a structure-based pharmacophore. This hypothesis was applied as a screening filter to Asinex and Chemdiv databases. Finally, 23 hits were tested in vitro. Among these, VH1019 and VH1011 induced a concentration-dependent strong broad antiproliferative effect in glioma (U87-MG), breast cancer (MCF-7), and prostate cancer (DU-145) cell lines as compared to nontumorigenic control, neonatal foreskin fibroblast (HFF-1). These compounds showed preferential growth inhibition of cancer cells over normal cells. The acetohydrazide derivative VH1019 was identified as a potential new chemotype for GRP78 inhibitors with an IC50 of 12.7 μM in MCF-7.
中文翻译：
GRP78靶向的新型抗癌药物的计算机虚拟筛选。
GRP78在多种神经胶质母细胞瘤，白血病，肺癌，前列腺癌，乳腺癌，胃癌和结肠癌中的过度表达使其成为抗癌药物开发的主要靶标。本研究报告使用计算机方法基于GRP78的新型抗癌药设计。作为这项工作的第一步，通过对接模拟对GRP78与15种已知配体之间的相互作用进行了建模。就其实验活性和能量指标而言，对接复合物GRP78-13优于其他化合物，被推导为基于结构的药效团。该假设被用作Asinex和Chemdiv数据库的筛选过滤器。最后，在体外测试了23个匹配。其中，VH1019和VH1011在神经胶质瘤（U87-MG），乳腺癌（MCF-7），与非致瘤性对照，新生儿包皮成纤维细胞（HFF-1）相比，可检测到前列腺癌（DU-145）细胞系。与正常细胞相比，这些化合物显示出对癌细胞的优先生长抑制作用。乙酰肼衍生物VH1019被确定为GRP78抑制剂的潜在新化学型，在MCF-7中的IC50为12.7μM。
更新日期：2018-05-31
中文翻译：
GRP78靶向的新型抗癌药物的计算机虚拟筛选。
GRP78在多种神经胶质母细胞瘤，白血病，肺癌，前列腺癌，乳腺癌，胃癌和结肠癌中的过度表达使其成为抗癌药物开发的主要靶标。本研究报告使用计算机方法基于GRP78的新型抗癌药设计。作为这项工作的第一步，通过对接模拟对GRP78与15种已知配体之间的相互作用进行了建模。就其实验活性和能量指标而言，对接复合物GRP78-13优于其他化合物，被推导为基于结构的药效团。该假设被用作Asinex和Chemdiv数据库的筛选过滤器。最后，在体外测试了23个匹配。其中，VH1019和VH1011在神经胶质瘤（U87-MG），乳腺癌（MCF-7），与非致瘤性对照，新生儿包皮成纤维细胞（HFF-1）相比，可检测到前列腺癌（DU-145）细胞系。与正常细胞相比，这些化合物显示出对癌细胞的优先生长抑制作用。乙酰肼衍生物VH1019被确定为GRP78抑制剂的潜在新化学型，在MCF-7中的IC50为12.7μM。
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