3GOL

HCV NS5b polymerase in complex with 1,5 benzodiazepine inhibitor (R)-11d

Summary for 3GOL

• Entry DOI: 10.2210/pdb3gol/pdb
• Related: 3CSO 3GNV 3GNW
• Descriptor: RNA-directed RNA polymerase, (11R)-10-acetyl-11-(2,4-dichlorophenyl)-6-hydroxy-3,3-dimethyl-2,3,4,5,10,11-hexahydro-1H-dibenzo[b,e][1,4]diazepin-1-one, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: 1, 5-benzodiazepine, hcv polymerase, ns5b, medicinal chemistry, 1b-j4, transferase
• Biological source: Hepatitis C virus isolate (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane ; Single-pass membrane protein . Core protein p19: Virion . Envelope glycoprotein E1: Virion membrane ; Single-pass type I membrane protein . Envelope glycoprotein E2: Virion membrane ; Single-pass type I membrane protein . p7: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Protease NS2-3: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Serine protease NS3: Host endoplasmic reticulum membrane ; Peripheral membrane protein . Non-structural protein 4A: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein . Non-structural protein 4B: Host endoplasmic reticulum membrane ; Multi-pass membrane protein . Non-structural protein 5A: Host endoplasmic reticulum membrane ; Peripheral membrane protein . RNA-directed RNA polymerase: Host endoplasmic reticulum membrane ; Single-pass type I membrane protein : O92972
• Total number of polymer chains: 2
• Total formula weight: 130573.81

Authors

Nyanguile, O.,De Bondt, H. (deposition date: 2009-03-19, release date: 2009-06-16, Last modification date: 2024-03-20)

Primary citation

McGowan, D.,Nyanguile, O.,Cummings, M.D.,Vendeville, S.,Vandyck, K.,Van den Broeck, W.,Boutton, C.W.,De Bondt, H.,Quirynen, L.,Amssoms, K.,Bonfanti, J.F.,Last, S.,Rombauts, K.,Tahri, A.,Hu, L.,Delouvroy, F.,Vermeiren, K.,Vandercruyssen, G.,Van der Helm, L.,Cleiren, E.,Mostmans, W.,Lory, P.,Pille, G.,Van Emelen, K.,Fanning, G.,Pauwels, F.,Lin, T.I.,Simmen, K.,Raboisson, P.
1,5-Benzodiazepine inhibitors of HCV NS5B polymerase.
Bioorg.Med.Chem.Lett., 19:2492-2496, 2009

PubMed Abstract: Optimization through parallel synthesis of a novel series of hepatitis C virus (HCV) NS5B polymerase inhibitors led to the identification of (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(6-methylpyridine-2-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zc and (R)-11-(4-benzyloxy-2-fluorophenyl)-6-hydroxy-3,3-dimethyl-10-(2,5-dimethyloxazol-4-carbonyl)-2,3,4,5,10,11-hexahydro-dibenzo[b,e][1,4]diazepin-1-one 11zk as potent (replicon EC(50)=400nM and 270nM, respectively) and selective (CC(50)>20muM) inhibitors of HCV replication. These data warrant further lead-optimization efforts.

PubMed: 19342234
DOI: 10.1016/j.bmcl.2009.03.035

Experimental method

X-RAY DIFFRACTION (2.85 Å)