2WCX

Crystal Structure of Hepatitis C Virus NS5B Polymerase in Complex with Thienopyrrole-Based Finger-Loop Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Optimization of Thienopyrrole-Based Finger-Loop Inhibitors of the Hepatitis C Virus Ns5B Polymerase.

Martin Hernando, J.I.Ontoria, J.M.Malancona, S.Attenni, B.Fiore, F.Bonelli, F.Koch, U.Di Marco, S.Colarusso, S.Ponzi, S.Gennari, N.Vignetti, S.E.Del Rosario Rico Ferreira, M.Habermann, J.Rowley, M.Narjes, F.

(2009) ChemMedChem 4: 1695

  • DOI: https://doi.org/10.1002/cmdc.200900184
  • Primary Citation of Related Structures:  
    2WCX

  • PubMed Abstract: 

    Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger-loop inhibitors based on a thieno[3,2-b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N-acetamides with submicromolar potency in the cell-based replicon assay, but they lacked oral bioavailability in rats. By linking the N4-position to the ortho-position of the C5-aryl group, we were able to identify the tetracyclic thienopyrrole 40, which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger-loop inhibitors based on an indole scaffold.


  • Organizational Affiliation

    Department of Medicinal Chemistry, Istituto di Ricerche di Biologia Molecolare P. Angeletti S.p.A. Merck Sharp & Dohme Research Laboratories Rome, Via Pontina km 30,600, 00040 Pomezia (Italy).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-DIRECTED RNA POLYMERASE537Hepatitis C virus (isolate BK)Mutation(s): 0 
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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
VGC
Query on VGC

Download Ideal Coordinates CCD File 
D [auth A]6-CYCLOHEXYL-4-METHYL-5-PHENYL-4H-THIENO[3,2-B]PYRROLE-2-CARBOXYLIC ACID
C20 H21 N O2 S
BNIGSPMLDODEAJ-UHFFFAOYSA-N
MN
Query on MN

Download Ideal Coordinates CCD File 
B [auth A],
C [auth A]
MANGANESE (II) ION
Mn
WAEMQWOKJMHJLA-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
VGC PDBBind:  2WCX IC50: 25 (nM) from 1 assay(s)
Binding MOAD:  2WCX IC50: 25 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.209 
  • R-Value Work: 0.167 
  • R-Value Observed: 0.169 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.407α = 90
b = 94.708β = 90
c = 95.54γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2009-08-18 
  • Deposition Author(s): Di Marco, S.

Revision History  (Full details and data files)

  • Version 1.0: 2009-08-18
    Type: Initial release
  • Version 1.1: 2011-11-23
    Changes: Atomic model, Database references, Derived calculations, Non-polymer description, Other, Refinement description, Structure summary, Version format compliance
  • Version 1.2: 2023-12-13
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description