State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China.
J Chem Inf Model. 2011 Nov 28;51(11):2939-47. doi: 10.1021/ci2002445. Epub 2011 Oct 21.
P90 ribosomal S6 kinase 2 (RSK2), which was shown to be overexpressed in human cancers, is a serine/threonine kinase and a potential target for cancer treatment. RSK2 comprises two terminal kinase domains (NTKD and CTKD) that can be inhibited by binding with different types of inhibitors at the ATP binding sites. In the absence of a crystal structure of RSK2, we constructed a model for the 3D structure of the RSK2 NTKD by homology modeling and stepwise constrained refinement with the reported inhibitors using a molecular docking method. Structure-based virtual screening was subsequently performed against a library containing commercially available compounds using the refined model. This resulted in the identification of seven novel RSK2 inhibitors with IC₅₀ values ranging from 2.4 to 14.45 μM.
P90 核糖体 S6 激酶 2（RSK2）在人类癌症中过度表达，它是一种丝氨酸/苏氨酸激酶，也是癌症治疗的潜在靶点。RSK2 包含两个末端激酶结构域（NTKD 和 CTKD），可通过在 ATP 结合位点与不同类型的抑制剂结合而被抑制。由于没有 RSK2 的晶体结构，我们通过同源建模和使用报道的抑制剂进行逐步约束细化，使用分子对接方法构建了 RSK2 NTKD 的三维结构模型。随后，使用细化模型对包含市售化合物的文库进行基于结构的虚拟筛选，从中鉴定出七种新型 RSK2 抑制剂，其 IC₅₀ 值范围为 2.4 至 14.45 μM。
