Xie Huan-Zhang, Li Lin-Li, Ren Ji-Xia, Zou Jun, Yang Li, Wei Yu-Quan, Yang Sheng-Yong
State Key Laboratory of Biotherapy, West China Hospital, West China School of Pharmacy, Sichuan University, Sichuan 610041, China.
Bioorg Med Chem Lett. 2009 Apr 1;19(7):1944-9. doi: 10.1016/j.bmcl.2009.02.049. Epub 2009 Feb 20.
In this investigation, chemical features based 3D pharmacophore models were developed based on the known inhibitors of Spleen tyrosine kinase (Syk) with the aid of hiphop and hyporefine modules within catalyst. The best quantitative pharmacophore model, Hypo1, was used as a 3D structural query for retrieving potential inhibitors from chemical 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 studies to refine the retrieved hits. Finally 30 compounds were selected from the top ranked hit compounds and conducted an in vitro kinase inhibitory assay. Six compounds showed a good inhibitory potency against Syk, which have been selected for further investigation.
在本研究中，借助Catalyst中的hiphop和hyporefine模块，基于已知的脾酪氨酸激酶（Syk）抑制剂开发了基于化学特征的3D药效团模型。最佳的定量药效团模型Hypo1用作3D结构查询，以从包括Specs、NCI、MayBridge和中国天然产物数据库（CNPD）在内的化学数据库中检索潜在抑制剂。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化合物。最后，从排名靠前的命中化合物中选择30种化合物，并进行体外激酶抑制试验。六种化合物对Syk显示出良好的抑制效力，已被选作进一步研究。
