Division of Informatics, GVK Biosciences Pvt. Ltd., S-1, Phase-1, T.I.E. Balanagar, Hyderabad 500037, Andhra Pradesh, India.
J Mol Graph Model. 2010 Feb 26;28(6):472-7. doi: 10.1016/j.jmgm.2009.11.002. Epub 2009 Nov 24.
Heat Shock Protein 90 (HSP90), an ATP-dependent molecular chaperone, has emerged as a promising target in the treatment of cancer. Inhibition of HSP90 represents a new target of antitumor therapy, since it may influence many specific signaling pathways. Many HSP90 inhibitors bind to the ATP-binding pocket, inhibit chaperone function, resulting in cell death. Recent clinical trials for treatment of cancer have put HSP90's importance into focus and have highlighted the need for full scale research into HSP90 related pathways. Here we report five novel HSP90 inhibitors which were identified by using pharmacophore models and docking studies. We used highly discriminative pharmacophore model as a 3D query to search against database of approximately 1 M compounds and cluster analysis results yielded 455 compounds which were further subjected for docking. Glide docking studies suggested 122 compounds as in silico hits and these compounds were further selected for the cytotoxicity assay in the HSP90-over expressing SKBr3 cell line. Of the 122 compounds tested, 5 compounds inhibited cell growth with an IC(50) value less than 50 microM.
热休克蛋白 90（HSP90）是一种 ATP 依赖性分子伴侣，已成为癌症治疗的一个有前途的靶点。HSP90 的抑制作用代表了抗肿瘤治疗的一个新靶点，因为它可能影响许多特定的信号通路。许多 HSP90 抑制剂结合到 ATP 结合口袋，抑制伴侣功能，导致细胞死亡。最近针对癌症治疗的临床试验使 HSP90 的重要性受到关注，并强调需要对 HSP90 相关途径进行全面研究。在这里，我们报告了通过药效基团模型和对接研究鉴定的五种新型 HSP90 抑制剂。我们使用高度区分的药效基团模型作为 3D 查询来搜索大约 100 万个化合物的数据库，聚类分析结果产生了 455 个化合物，这些化合物进一步进行了对接。Glide 对接研究表明，有 122 个化合物为计算机筛选命中，这些化合物进一步被选择用于 HSP90 过表达 SKBr3 细胞系的细胞毒性测定。在测试的 122 种化合物中，有 5 种化合物的 IC50 值小于 50μM，抑制细胞生长。
