2IJN

Isothiazoles as active-site inhibitors of HCV NS5B polymerase

Summary for 2IJN

• Entry DOI: 10.2210/pdb2ijn/pdb
• Related: 2HWH 2HWI 2I1R
• Descriptor: RNA polymerase NS5B, (2R,3R)-3-{[3,5-BIS(TRIFLUOROMETHYL)PHENYL]AMINO}-2-CYANO-3-THIOXOPROPANAMIDE (3 entities in total)
• Functional Keywords: hcv; ns5b; viral rna directed rna polymerase; rdrp; active site; covalent inhibitor, transcription, transferase
• Biological source: Hepatitis C virus subtype 1b
• Total number of polymer chains: 2
• Total formula weight: 128741.20

Authors

Yan, S.,Yao, N. (deposition date: 2006-09-29, release date: 2006-11-28, Last modification date: 2024-11-20)

Primary citation

Yan, S.,Appleby, T.,Gunic, E.,Shim, J.H.,Tasu, T.,Kim, H.,Rong, F.,Chen, H.,Hamatake, R.,Wu, J.Z.,Hong, Z.,Yao, N.
Isothiazoles as active-site inhibitors of HCV NS5B polymerase
Bioorg.Med.Chem.Lett., 17:28-33, 2007

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.

PubMed: 17049853
DOI: 10.1016/j.bmcl.2006.10.002

Experimental method

X-RAY DIFFRACTION (2.2 Å)