3SKE

I. Novel HCV NS5B Polymerase Inhibitors: Discovery of Indole 2- Carboxylic Acids with C3-Heterocycles

Summary for 3SKE

• Entry DOI: 10.2210/pdb3ske/pdb
• Related: 3SKA 3SKH
• Descriptor: HCV NS5B RNA_DEPENDENT RNA POLYMERASE, PHOSPHATE ION, 1-[(2-aminopyridin-4-yl)methyl]-3-(2,4-dioxo-1,2-dihydrothieno[3,4-d]pyrimidin-3(4H)-yl)-5-(trifluoromethyl)-1H-indole-2-carboxylic acid, ... (4 entities in total)
• Functional Keywords: rna-dependent rna polymerase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepatitis C virus isolate HC-J4 (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein (By similarity). 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): O92972
• Total number of polymer chains: 2
• Total formula weight: 129481.01

Authors

Lesburg, C.A.,Anilkumar, G.N. (deposition date: 2011-06-22, release date: 2011-08-31, Last modification date: 2024-11-27)

Primary citation

Anilkumar, G.N.,Lesburg, C.A.,Selyutin, O.,Rosenblum, S.B.,Zeng, Q.,Jiang, Y.,Chan, T.Y.,Pu, H.,Vaccaro, H.,Wang, L.,Bennett, F.,Chen, K.X.,Duca, J.,Gavalas, S.,Huang, Y.,Pinto, P.,Sannigrahi, M.,Velazquez, F.,Venkatraman, S.,Vibulbhan, B.,Agrawal, S.,Butkiewicz, N.,Feld, B.,Ferrari, E.,He, Z.,Jiang, C.K.,Palermo, R.E.,McMonagle, P.,Huang, H.C.,Shih, N.Y.,Njoroge, G.,Kozlowski, J.A.
I. Novel HCV NS5B polymerase inhibitors: discovery of indole 2-carboxylic acids with C3-heterocycles.
Bioorg.Med.Chem.Lett., 21:5336-5341, 2011

PubMed Abstract: SAR development of indole-based palm site inhibitors of HCV NS5B polymerase exemplified by initial indole lead 1 (NS5B IC(50)=0.9 μM, replicon EC(50)>100 μM) is described. Structure-based drug design led to the incorporation of novel heterocyclic moieties at the indole C3-position which formed a bidentate interaction with the protein backbone. SAR development resulted in leads 7q (NS5B IC(50)=0.032 μM, replicon EC(50)=1.4 μM) and 7r (NS5B IC(50)=0.017 μM, replicon EC(50)=0.3 μM) with improved enzyme and replicon activity.

PubMed: 21840715
DOI: 10.1016/j.bmcl.2011.07.021

Experimental method

X-RAY DIFFRACTION (1.97 Å)