Wang Hui-Yuan, Cao Zhi-Xing, Li Lin-Li, Jiang Pei-Du, Zhao Ying-Lan, Luo Shi-Dong, Yang Li, Wei Yu-Quan, Yang Sheng-Yong
State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, Keyuan Road 4, Chengdu, Sichuan 610041, China.
Bioorg Med Chem Lett. 2008 Sep 15;18(18):4972-7. doi: 10.1016/j.bmcl.2008.08.033. Epub 2008 Aug 14.
Pharmacophore models of Polo-like kinase-1 (PLK1) inhibitors have been established by using the HipHop and HypoGen algorithms implemented in the Catalyst software package. The best quantitative pharmacophore model, Hypo1, which has the highest correlation coefficient (0.9895), consists of one hydrogen bond acceptor, one hydrogen bond donor, one hydrophobic feature, and one hydrophobic aliphatic feature. Hypo1 was further validated by test set and cross validation method. Then Hypo1 was used as a 3D query to screen several databases including Specs, NCI, Maybridge, and Chinese Nature Product Database (CNPD). The hit compounds were subsequently subjected to filtering by Lipinski's rule of five and docking study to refine the retrieved hits and as a result to reduce the rate of false positive. Finally, a total of 20 compounds were selected and have been shifted to in vitro and in vivo studies. As far as we know, this is the first report on the pharmacophore modeling even the first publicly reported virtual screening study of PLK1 inhibitors.
通过使用Catalyst软件包中实现的HipHop和HypoGen算法，已建立了Polo样激酶-1（PLK1）抑制剂的药效团模型。最佳的定量药效团模型Hypo1，其相关系数最高（0.9895），由一个氢键受体、一个氢键供体、一个疏水特征和一个疏水脂肪族特征组成。Hypo1通过测试集和交叉验证方法进一步验证。然后将Hypo1用作三维查询，以筛选包括Specs、NCI、Maybridge和中国天然产物数据库（CNPD）在内的多个数据库。随后，对命中的化合物进行Lipinski五规则过滤和对接研究，以优化检索到的命中结果，从而降低假阳性率。最后，总共选择了20种化合物，并已转入体外和体内研究。据我们所知，这是关于药效团建模的首次报告，甚至是首次公开报道的PLK1抑制剂虚拟筛选研究。
