3H5U

Hepatitis C virus polymerase NS5B with saccharin inhibitor 1

Summary for 3H5U

• Entry DOI: 10.2210/pdb3h5u/pdb
• Related: 2GIQ 3G86 3H59 3H5S
• Descriptor: RNA-directed RNA polymerase, N-({3-[(5S)-5-tert-butyl-1-(4-fluorobenzyl)-4-hydroxy-2-oxo-2,5-dihydro-1H-pyrrol-3-yl]-1,1-dioxido-1,2-benzisothiazol-7-yl}methyl)methanesulfonamide (3 entities in total)
• Functional Keywords: hcv, hepatitis, ns5b, transferase rna-dependent rna polymerase, acetylation, apoptosis, atp-binding, capsid protein, cell membrane, cytoplasm, disulfide bond, endoplasmic reticulum, envelope protein, fusion protein, glycoprotein, helicase, host-virus interaction, hydrolase, interferon antiviral system evasion, lipid droplet, lipoprotein, membrane, metal-binding, mitochondrion, multifunctional enzyme, nucleotide-binding, nucleotidyltransferase, nucleus, oncogene, palmitate, phosphoprotein, protease, ribonucleoprotein, rna replication, rna-binding, rna-directed rna polymerase, secreted, serine protease, sh3-binding, thiol protease, transcription, transcription regulation, transferase, transmembrane, ubl conjugation, viral nucleoprotein, virion, zinc
• 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: 129424.52

Authors

Harris, S.F.,Ghate, M. (deposition date: 2009-04-22, release date: 2009-09-08, Last modification date: 2024-02-21)

Primary citation

de Vicente, J.,Hendricks, R.T.,Smith, D.B.,Fell, J.B.,Fischer, J.,Spencer, S.R.,Stengel, P.J.,Mohr, P.,Robinson, J.E.,Blake, J.F.,Hilgenkamp, R.K.,Yee, C.,Adjabeng, G.,Elworthy, T.R.,Li, J.,Wang, B.,Bamberg, J.T.,Harris, S.F.,Wong, A.,Leveque, V.J.,Najera, I.,Le Pogam, S.,Rajyaguru, S.,Ao-Ieong, G.,Alexandrova, L.,Larrabee, S.,Brandl, M.,Briggs, A.,Sukhtankar, S.,Farrell, R.
Non-nucleoside inhibitors of HCV polymerase NS5B. Part 4: structure-based design, synthesis, and biological evaluation of benzo[d]isothiazole-1,1-dioxides
Bioorg.Med.Chem.Lett., 19:5652-5656, 2009

PubMed Abstract: A series of benzo[d]isothiazole-1,1-dioxides were designed and evaluated as inhibitors of HCV polymerase NS5B. Structure-based design led to the incorporation of a high affinity methyl sulfonamide group. Structure-activity relationship (SAR) studies of this series revealed analogues with submicromolar potencies in the HCV replicon assay and moderate pharmacokinetic properties. SAR studies combined with structure based drug design focused on the sulfonamide region led to a novel and potent cyclic analogue.

PubMed: 19709881
DOI: 10.1016/j.bmcl.2009.08.022

Experimental method

X-RAY DIFFRACTION (1.95 Å)