3LKH

Inhibitors of Hepatitis C Virus Polymerase: Synthesis and Characterization of Novel 6-Fluoro-N-[2-Hydroxy-1(S)-Benzamides

Summary for 3LKH

• Entry DOI: 10.2210/pdb3lkh/pdb
• Descriptor: RNA-directed RNA polymerase, 2-(2-{[(1S)-1-benzyl-2-hydroxyethyl]amino}-2-oxoethoxy)-N-butyl-6-fluoro-N-methylbenzamide (3 entities in total)
• Functional Keywords: hcv, ns5b, polymerase, acetylation, apoptosis, atp-binding, capsid protein, envelope protein, fusion protein, glycoprotein, helicase, host cell membrane, host cytoplasm, host endoplasmic reticulum, host lipid droplet, host membrane, host mitochondrion, host nucleus, host-virus interaction, hydrolase, interferon antiviral system evasion, lipoprotein, membrane, metal-binding, multifunctional enzyme, nucleotide-binding, nucleotidyltransferase, oncogene, palmitate, phosphoprotein, protease, ribonucleoprotein, rna replication, rna-binding, rna-directed rna polymerase, secreted, serine protease, sh3-binding, thiol protease, transcription, transcription regulation, transferase, transmembrane, ubl conjugation, viral nucleoprotein, virion, zinc
• 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: 129216.14

Authors

Lesburg, C.A. (deposition date: 2010-01-27, release date: 2010-03-23, Last modification date: 2024-10-30)

Primary citation

Cheng, C.C.,Shipps, G.W.,Yang, Z.,Kawahata, N.,Lesburg, C.A.,Duca, J.S.,Bandouveres, J.,Bracken, J.D.,Jiang, C.K.,Agrawal, S.,Ferrari, E.,Huang, H.C.
Inhibitors of hepatitis C virus polymerase: synthesis and characterization of novel 2-oxy-6-fluoro-N-((S)-1-hydroxy-3-phenylpropan-2-yl)-benzamides.
Bioorg.Med.Chem.Lett., 20:2119-2124, 2010

PubMed Abstract: SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)benzamide (1), identified using our proprietary automated ligand identification system (ALIS),(1) has led to a novel series of selective hepatitis C virus (HCV) NS5B polymerase inhibitors with improved in vitro potency as exemplified by (S)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)-N-isopentyl-N-methylbenzamidecarboxamide (41) (IC(50)=0.5 microM). The crystal structure of an analogue (44) was solved and provided rationalization of the SAR of this series, which binds in a distinct manner in the palm domain of NS5B, consistent with biochemical analysis using enzyme mutant variants. These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase.

PubMed: 20219368
DOI: 10.1016/j.bmcl.2010.02.054

Experimental method

X-RAY DIFFRACTION (2.05 Å)