3D28

Crystal structure of hcv ns5b polymerase with a novel benzisothiazole inhibitor

Summary for 3D28

• Entry DOI: 10.2210/pdb3d28/pdb
• Related: 3BR9 3BSA 3BSC 3CDE 3CO9 3CVK 3CWJ
• Descriptor: RNA-directed RNA polymerase, (5S)-1-benzyl-3-(1,1-dioxido-1,2-benzisothiazol-3-yl)-4-hydroxy-5-(1-methylethyl)-1,5-dihydro-2H-pyrrol-2-one (3 entities in total)
• Functional Keywords: protein-ligand complex, rna-directed rna polymerase, nucleotidyltransferase, nucleotide-binding, transcription, hydrolase, transferase
• Biological source: Hepatitis C virus (isolate BK) (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. Core protein p19: Virion (By similarity). Envelope glycoprotein E1: Virion membrane; Single-pass type I membrane protein (Potential). Envelope glycoprotein E2: Virion membrane; Single-pass type I membrane protein (Potential). p7: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Protease NS2-3: Host endoplasmic reticulum membrane; Multi-pass membrane protein (Potential). Serine protease NS3: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). Non-structural protein 4A: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential). Non-structural protein 4B: Host endoplasmic reticulum membrane; Multi-pass membrane protein (By similarity). Non-structural protein 5A: Host endoplasmic reticulum membrane; Peripheral membrane protein (By similarity). RNA-directed RNA polymerase: Host endoplasmic reticulum membrane; Single-pass type I membrane protein (Potential): P26663
• Total number of polymer chains: 2
• Total formula weight: 129484.40

Authors

Han, Q.,Showalter, R.E.,Zhao, Q.,Kissinger, C.R. (deposition date: 2008-05-07, release date: 2009-05-19, Last modification date: 2024-04-03)

Primary citation

Kim, S.H.,Tran, M.T.,Ruebsam, F.,Xiang, A.X.,Ayida, B.,McGuire, H.,Ellis, D.,Blazel, J.,Tran, C.V.,Murphy, D.E.,Webber, S.E.,Zhou, Y.,Shah, A.M.,Tsan, M.,Showalter, R.E.,Patel, R.,Gobbi, A.,LeBrun, L.A.,Bartkowski, D.M.,Nolan, T.G.,Norris, D.A.,Sergeeva, M.V.,Kirkovsky, L.,Zhao, Q.,Han, Q.,Kissinger, C.R.
Structure-based design, synthesis, and biological evaluation of 1,1-dioxoisothiazole and benzo[b]thiophene-1,1-dioxide derivatives as novel inhibitors of hepatitis C virus NS5B polymerase.
Bioorg.Med.Chem.Lett., 18:4181-4185, 2008

PubMed Abstract: A novel series of HCV NS5B polymerase inhibitors comprising 1,1-dioxoisothiazoles and benzo[b]thiophene-1,1-dioxides were designed, synthesized, and evaluated. SAR studies guided by structure-based design led to the identification of a number of potent NS5B inhibitors with nanomolar IC(50) values. The most potent compound exhibited IC(50) less than 10nM against the genotype 1b HCV polymerase and EC(50) of 70 nM against a genotype 1b replicon in cell culture. The DMPK properties of selected compounds were also evaluated.

PubMed: 18554907
DOI: 10.1016/j.bmcl.2008.05.083

Experimental method

X-RAY DIFFRACTION (2.3 Å)