2YOJ

HCV NS5B polymerase complexed with pyridonylindole compound

Summary for 2YOJ

• Entry DOI: 10.2210/pdb2yoj/pdb
• Descriptor: RNA-DIRECTED RNA POLYMERASE, 4-fluoranyl-6-[(7-fluoranyl-4-oxidanylidene-3H-quinazolin-6-yl)methyl]-8-(2-oxidanylidene-1H-pyridin-3-yl)furo[2,3-e]indole-7-carboxylic acid, PHOSPHATE ION, ... (4 entities in total)
• Functional Keywords: transferase, inhibitor
• Biological source: HEPATITIS C VIRUS
• 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: 131996.29

Authors

Chen, K.X.,Venkatraman, S.,Anilkumar, G.N.,Zeng, Q.,Lesburg, C.A.,Vibulbhan, B.,Yang, W.,Velazquez, F.,Chan, T.-Y.,Bennett, F.,Sannigrahi, M.,Jiang, Y.,Duca, J.S.,Pinto, P.,Gavalas, S.,Huang, Y.,Wu, W.,Selyutin, O.,Agrawal, S.,Feld, B.,Huang, H.-C.,Li, C.,Cheng, K.-C.,Shih, N.-Y.,Kozlowski, J.A.,Rosenblum, S.B.,Njoroge, F.G. (deposition date: 2012-10-24, release date: 2013-10-09, Last modification date: 2024-05-08)

Primary citation

Chen, K.X.,Venkatraman, S.,Anilkumar, G.N.,Zeng, Q.,Lesburg, C.A.,Vibulbhan, B.,Velazquez, F.,Chan, T.-Y.,Bennett, F.,Jiang, Y.,Pinto, P.,Huang, Y.,Selyutin, O.,Agrawal, S.,Huang, H.-C.,Li, C.,Cheng, K.-C.,Shih, N.-Y.,Kozlowski, J.A.,Rosenblum, S.B.,Njoroge, F.G.
Discovery of Sch 900188: A Potent Hepatitis C Virus Ns5B Polymerase Inhibitor Prodrug as a Development Candidate
Acs Med.Chem.Lett., 5:244-, 2014

PubMed Abstract: Starting from indole-based hepatitis C virus (HCV) NS5B polymerase inhibitor lead compound 1, structure modifications were performed at multiple indole substituents to improve potency and pharmacokinetic (PK) properties. Bicyclic quinazolinone was found to be the best substituent at indole nitrogen, while 4,5-furanylindole was identified as the best core. Compound 11 demonstrated excellent potency. Its C2 N,N-dimethylaminoethyl ester prodrug 12 (SCH 900188) demonstrated significant improvement in PK and was selected as the development candidate.

PubMed: 24900812
DOI: 10.1021/ML400192W

Experimental method

X-RAY DIFFRACTION (1.76 Å)