3MF5

Hepatitis C virus polymerase NS5B (BK) with amide bioisostere thumb site inhibitor

Summary for 3MF5

• Entry DOI: 10.2210/pdb3mf5/pdb
• Related: 2GIR
• Descriptor: RNA-directed RNA polymerase, 3-[2-(trans-4-methylcyclohexyl)phenyl]-5-phenylthiophene-2-carboxylic acid, GLYCEROL, ... (4 entities in total)
• Functional Keywords: hcv, hepatitis, ns5b, transferase rna-dependent rna polymerase, transferase
• Biological source: Hepatitis C virus (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: 127554.55

Authors

Harris, S.F.,Tavares, G.,Ghate, M. (deposition date: 2010-04-01, release date: 2010-07-28, Last modification date: 2024-02-21)

Primary citation

Yang, H.,Hendricks, R.T.,Arora, N.,Nitzan, D.,Yee, C.,Lucas, M.C.,Yang, Y.,Fung, A.,Rajyaguru, S.,Harris, S.F.,Leveque, V.J.,Hang, J.Q.,Pogam, S.L.,Reuter, D.,Tavares, G.A.
Cyclic amide bioisosterism: Strategic application to the design and synthesis of HCV NS5B polymerase inhibitors.
Bioorg.Med.Chem.Lett., 20:4614-4619, 2010

PubMed Abstract: Conformational modeling has been successfully applied to the design of cyclic bioisosteres used to replace a conformationally rigid amide bond in a series of thiophene carboxylate inhibitors of HCV NS5B polymerase. Select compounds were equipotent with the original amide series. Single-point mutant binding studies, in combination with inhibition structure-activity relationships, suggest this new series interacts at the Thumb-II domain of NS5B. Inhibitor binding at the Thumb-II site was ultimately confirmed by solving a crystal structure of 8b complexed with NS5B.

PubMed: 20584604
DOI: 10.1016/j.bmcl.2010.06.008

Experimental method

X-RAY DIFFRACTION (2 Å)