3MF5

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


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.186 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Cyclic amide bioisosterism: Strategic application to the design and synthesis of HCV NS5B polymerase inhibitors.

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.

(2010) Bioorg Med Chem Lett 20: 4614-4619

  • DOI: https://doi.org/10.1016/j.bmcl.2010.06.008
  • Primary Citation of Related Structures:  
    3MF5

  • 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.


  • Organizational Affiliation

    Medicinal Chemistry Department, Roche Palo Alto, LLC, Palo Alto, CA 94304, USA. Hanbiaoyang@gmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase
A, B
570Hepatitis C virus (isolate BK)Mutation(s): 0 
Gene Names: NS5B
EC: 2.7.7.48
UniProt
Find proteins for P26663 (Hepatitis C virus genotype 1b (isolate BK))
Explore P26663 
Go to UniProtKB:  P26663
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26663
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
HJZ PDBBind:  3MF5 Kd: 4320 (nM) from 1 assay(s)
Binding MOAD:  3MF5 IC50: 42 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.222 
  • R-Value Work: 0.186 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 85.447α = 90
b = 105.363β = 90
c = 126.119γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-07-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2024-02-21
    Changes: Data collection, Database references, Derived calculations