3U4R

Novel HCV NS5B polymerase Inhibitors: Discovery of Indole C2 Acyl sulfonamides

Summary for 3U4R

• Entry DOI: 10.2210/pdb3u4r/pdb
• Related: 3U4O
• Descriptor: RNA-directed RNA polymerase, 1-[(2-aminopyridin-4-yl)methyl]-5-chloro-N-({3-[(methylsulfonyl)amino]phenyl}sulfonyl)-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxamide (3 entities in total)
• Functional Keywords: nucleotidyl transfer, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepatitis C virus (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: 130189.99

Authors

Anilkumar, G.N.,Selyutin, O.,Rosenblum, S.B.,Zeng, Q.,Jiang, Y.,Chan, T.-Y.,Pu, H.,Wang, L.,Bennett, F.,Chen, K.X.,Lesburg, C.A.,Duca, J.S.,Gavalas, S.,Huang, Y.,Pinto, P.,Sannagrahi, M.,Velazquez, F.,Venkataraman, S.,Vilbubhan, B.,Agrawal, S.,Ferrari, E.,Jiang, C.-K.,Huang, H.-C.,Shih, N.-Y.,Njoroge, F.G.,Kozlowski, J.A. (deposition date: 2011-10-10, release date: 2011-12-07, Last modification date: 2024-02-28)

Primary citation

Anilkumar, G.N.,Selyutin, O.,Rosenblum, S.B.,Zeng, Q.,Jiang, Y.,Chan, T.Y.,Pu, H.,Wang, L.,Bennett, F.,Chen, K.X.,Lesburg, C.A.,Duca, J.,Gavalas, S.,Huang, Y.,Pinto, P.,Sannigrahi, M.,Velazquez, F.,Venkatraman, S.,Vibulbhan, B.,Agrawal, S.,Ferrari, E.,Jiang, C.K.,Huang, H.C.,Shih, N.Y.,George Njoroge, F.,Kozlowski, J.A.
II. Novel HCV NS5B polymerase inhibitors: Discovery of indole C2 acyl sulfonamides.
Bioorg.Med.Chem.Lett., 22:713-717, 2012

PubMed Abstract: Development of SAR at the C2 position of indole lead 1, a palm site inhibitor of HCV NS5B polymerase (NS5B IC(50)=0.053μM, replicon EC(50)=4.8μM), is described. Initial screening identified an acyl sulfonamide moiety as an isostere for the C2 carboxylic acid group. Further SAR investigation resulted in identification of acyl sufonamide analog 7q (NS5B IC(50)=0.039μM, replicon EC(50)=0.011μM) with >100-fold improved replicon activity.

PubMed: 22104146
DOI: 10.1016/j.bmcl.2011.10.041

Experimental method

X-RAY DIFFRACTION (2 Å)