3CDE

Crystal structure of HCV NS5B polymerase with a novel Pyridazinone inhibitor

Summary for 3CDE

• Entry DOI: 10.2210/pdb3cde/pdb
• Related: 3BR9 3BSA 3BSC
• Descriptor: RNA-directed RNA polymerase, N-{3-[5-hydroxy-2-(3-methylbutyl)-3-oxo-6-thiophen-2-yl-2,3-dihydropyridazin-4-yl]-1,1-dioxido-2H-1,2,4-benzothiadiazin-7-yl}methanesulfonamide (3 entities in total)
• Functional Keywords: protein-ligand complex, rna replication, rna-binding, rna-directed rna polymerase, atp-binding, host-virus interaction, hydrolase, metal-binding, nucleotide-binding, nucleotidyltransferase, ribonucleoprotein, transcription, transcription regulation, transferase, viral nucleoprotein, virion
• Biological source: Hepatitis C virus
• 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: 129766.74

Authors

Zhao, Q.,Showalter, R.E.,Han, Q.,Kissinger, C.R. (deposition date: 2008-02-26, release date: 2009-03-03, Last modification date: 2024-04-03)

Primary citation

Li, L.S.,Zhou, Y.,Murphy, D.E.,Stankovic, N.,Zhao, J.,Dragovich, P.S.,Bertolini, T.,Sun, Z.,Ayida, B.,Tran, C.V.,Ruebsam, F.,Webber, S.E.,Shah, A.M.,Tsan, M.,Showalter, R.E.,Patel, R.,Lebrun, L.A.,Bartkowski, D.M.,Nolan, T.G.,Norris, D.A.,Kamran, R.,Brooks, J.,Sergeeva, M.V.,Kirkovsky, L.,Zhao, Q.,Kissinger, C.R.
Novel HCV NS5B polymerase inhibitors derived from 4-(1',1'-dioxo-1',4'-dihydro-1'lambda(6)-benzo[1',2',4']thiadiazin-3'-yl)-5-hydroxy-2H-pyridazin-3-ones. Part 3: Further optimization of the 2-, 6-, and 7'-substituents and initial pharmacokinetic assessments.
Bioorg.Med.Chem.Lett., 18:3446-3455, 2008

PubMed Abstract: 5-Hydroxy-3(2H)-pyridazinone derivatives were investigated as inhibitors of genotype 1 HCV NS5B polymerase. Lead optimization led to the discovery of compound 3a, which displayed potent inhibitory activities in biochemical and replicon assays [IC(50) (1b)<10nM; IC(50) (1a)=22 nM; EC(50) (1b)=5nM], good stability toward human liver microsomes (HLM t(1/2)>60 min), and high ratios of liver to plasma concentrations 12h after a single oral administration to rats.

PubMed: 18457949
DOI: 10.1016/j.bmcl.2008.02.072

Experimental method

X-RAY DIFFRACTION (2.1 Å)