Isothiazoles as active-site inhibitors of HCV NS5B polymerase.
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Yan S, Appleby T, Gunic E, Shim JH, Tasu T, Kim H, Rong F, Chen H, Hamatake R, Wu JZ, Hong Z, Yao N
Isothiazoles as active-site inhibitors of HCV NS5B polymerase.
Bioorg Med Chem Lett. 2007 Jan 1;17(1):28-33. Epub 2006 Oct 5.
- PubMed ID
- 17049853 [ View in PubMed]
- 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.