2wcx

Crystal Structure of Hepatitis C Virus NS5B Polymerase in Complex with Thienopyrrole-Based Finger-Loop Inhibitors

spinqualitylabelsall models 2wcx, resolution 2.00Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2wcx is a 1 chain structure with sequence from Hcv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: MN, VGC Related: 1nhu, 2i1r, 1jxp, 2jc1, 1gx6, 1a1q, 1c2p, 1cu1, 1ns3, 2jc0, 2ax1, 1nhv, 1csj, 2brl, 2brk, 1gx5, 2ax0, 2awz, 1quv, 1os5 Activity: RNA-directed RNA polymerase, with EC number 2.7.7.48 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger-loop inhibitors based on a thieno[3,2-b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N-acetamides with submicromolar potency in the cell-based replicon assay, but they lacked oral bioavailability in rats. By linking the N4-position to the ortho-position of the C5-aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger-loop inhibitors based on an indole scaffold. Optimization of Thienopyrrole-Based Finger-Loop Inhibitors of the Hepatitis C Virus NS5B Polymerase.,Martin Hernando JI, Ontoria JM, Malancona S, Attenni B, Fiore F, Bonelli F, Koch U, Di Marco S, Colarusso S, Ponzi S, Gennari N, Vignetti SE, Rico Ferreira MD, Habermann J, Rowley M, Narjes F ChemMedChem. 2009 Aug 11. PMID:19672916 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also RNA polymerase

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