4EO6

HCV NS5B polymerase inhibitors: Tri-substituted acylhydrazines as tertiary amide bioisosteres

Summary for 4EO6

• Entry DOI: 10.2210/pdb4eo6/pdb
• Related: 4EO8
• Descriptor: RNA-directed RNA polymerase, 5-(3,3-dimethylbut-1-yn-1-yl)-3-{[(trans-4-methylcyclohexyl)carbonyl](propan-2-yl)amino}thiophene-2-carboxylic acid (3 entities in total)
• Functional Keywords: hcv, ns5b, rna, rna polymerase, polymerase inhibitor, thumb site 2 inhibitor, rna-dependent rna polymerase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Hepatitis C virus (isolate BK) (HCV)
• Cellular location: Core protein p21: Host endoplasmic reticulum membrane; Single-pass membrane protein. 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): P26663
• Total number of polymer chains: 2
• Total formula weight: 129068.14

Authors

Appleby, T.C.,Canales, E.,Watkins, W.J. (deposition date: 2012-04-13, release date: 2012-06-27, Last modification date: 2024-10-30)

Primary citation

Canales, E.,Carlson, J.S.,Appleby, T.,Fenaux, M.,Lee, J.,Tian, Y.,Tirunagari, N.,Wong, M.,Watkins, W.J.
Tri-substituted acylhydrazines as tertiary amide bioisosteres: HCV NS5B polymerase inhibitors.
Bioorg.Med.Chem.Lett., 22:4288-4292, 2012

PubMed Abstract: The use of a tri-substituted acylhydrazine as an isostere of a tertiary amide was explored in a series of HCV NS5B thumb site II inhibitors. Direct replacement generated an analog with similar conformational and physicochemical properties. The series was extended to produce compounds with potent binding affinities and encouraging levels of cellular potency.

PubMed: 22664130
DOI: 10.1016/j.bmcl.2012.05.025

Experimental method

X-RAY DIFFRACTION (1.791 Å)