Yan Shunqi, Appleby Todd, Gunic Esmir, Shim Jae Hoon, Tasu Tania, Kim Hongwoo, Rong Frank, Chen Huaming, Hamatake Robert, Wu Jim Z, Hong Zhi, Yao Nanhua
Valeant Pharmaceutical Research and Development, 3300 Hyland Ave., Costa Mesa, CA 92626, USA.
Bioorg Med Chem Lett. 2007 Jan 1;17(1):28-33. doi: 10.1016/j.bmcl.2006.10.002. Epub 2006 Oct 5.
Isothiazole analogs were discovered as a novel class of active-site inhibitors of HCV NS5B polymerase. The best compound has an IC(50) of 200 nM and EC(50) of 100 nM, which is a significant improvement over the starting inhibitor (1). The X-ray complex structure of 1 with HCV NS5B was obtained at a resolution of 2.2A, revealing that the inhibitor is covalently linked with Cys 366 of the 'primer-grip'. Furthermore, it makes considerable contacts with the C-terminus, beta-loop, and more importantly, to the active-site of the enzyme. The uniqueness of this binding mode offers a new insight for the rational design of novel inhibitors for HCV NS5B polymerase.
异噻唑类似物被发现是一类新型的丙型肝炎病毒（HCV）NS5B聚合酶活性位点抑制剂。最佳化合物的半数抑制浓度（IC50）为200 nM，半数有效浓度（EC50）为100 nM，相较于起始抑制剂有显著改善（1）。以2.2埃的分辨率获得了化合物1与HCV NS5B的X射线复合物结构，结果显示该抑制剂与“引物结合区”的半胱氨酸366共价连接。此外，它与C末端、β环有大量接触，更重要的是，与酶的活性位点有接触。这种结合模式的独特性为合理设计新型HCV NS5B聚合酶抑制剂提供了新的思路。
