4MZ4

Discovery of an Irreversible HCV NS5B Polymerase Inhibitor

Summary for 4MZ4

• Entry DOI: 10.2210/pdb4mz4/pdb
• Descriptor: RNA-directed RNA polymerase, 1-[(2-chloroquinolin-3-yl)methyl]-6-fluoro-5-methyl-3-(2-oxo-1,2-dihydropyridin-3-yl)-1H-indole-2-carboxylic acid, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: rna-dependent rna polymerase, 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: 129591.82

Authors

Zeng, Q.,Anilkumar, G.N.,Rosenblum, S.B.,Huang, H.-C.,Lesburg, C.A.,Jiang, Y.,Selyutin, O.,Chan, T.-Y.,Bennett, F.,Chen, K.X.,Venkatraman, S.,Sannigrahi, M.,Velazquez, F.,Duca, J.S.,Gavalas, S.,Huang, Y.,Pu, H.,Wang, L.,Pinto, P.,Vibulbhan, B.,Agrawal, S.,Ferrari, E.,Jiang, C.-K.,Li, C.,Hesk, D.,Gesell, J.,Sorota, S.,Shih, N.-Y.,Njoroge, F.G.,Kozlowski, J.A. (deposition date: 2013-09-29, release date: 2013-12-11, Last modification date: 2024-11-06)

Primary citation

Zeng, Q.,Nair, A.G.,Rosenblum, S.B.,Huang, H.C.,Lesburg, C.A.,Jiang, Y.,Selyutin, O.,Chan, T.Y.,Bennett, F.,Chen, K.X.,Venkatraman, S.,Sannigrahi, M.,Velazquez, F.,Duca, J.S.,Gavalas, S.,Huang, Y.,Pu, H.,Wang, L.,Pinto, P.,Vibulbhan, B.,Agrawal, S.,Ferrari, E.,Jiang, C.K.,Li, C.,Hesk, D.,Gesell, J.,Sorota, S.,Shih, N.Y.,Njoroge, F.G.,Kozlowski, J.A.
Discovery of an irreversible HCV NS5B polymerase inhibitor.
Bioorg.Med.Chem.Lett., 23:6585-6587, 2013

PubMed Abstract: The discovery of lead compound 2e was described. Its covalent binding to HCV NS5B polymerase enzyme was investigated by X-ray analysis. The results of distribution, metabolism and pharmacokinetics were reported. Compound 2e was demonstrated to be potent (replicon GT-1b EC50 = 0.003 μM), highly selective, and safe in in vitro and in vivo assays.

PubMed: 24252545
DOI: 10.1016/j.bmcl.2013.10.060

Experimental method

X-RAY DIFFRACTION (1.63 Å)