Isothiazoles as active-site inhibitors of HCV NS5B polymerase |
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Authors: | 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 |
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Institution: | Valeant Pharmaceutical Research and Development, 3300 Hyland Ave., Costa Mesa, CA 92626, USA. syan@valeant.com |
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Abstract: | 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. |
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