3Q0Z

Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with (2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5h-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


This is version 1.2 of the entry. See complete history


Literature

Syntheses and initial evaluation of a series of indolo-fused heterocyclic inhibitors of the polymerase enzyme (NS5B) of the hepatitis C virus.

Zheng, X.Hudyma, T.W.Martin, S.W.Bergstrom, C.Ding, M.He, F.Romine, J.Poss, M.A.Kadow, J.F.Chang, C.H.Wan, J.Witmer, M.R.Morin, P.Camac, D.M.Sheriff, S.Beno, B.R.Rigat, K.L.Wang, Y.K.Fridell, R.Lemm, J.Qiu, D.Liu, M.Voss, S.Pelosi, L.Roberts, S.B.Gao, M.Knipe, J.Gentles, R.G.

(2011) Bioorg Med Chem Lett 21: 2925-2929

  • DOI: https://doi.org/10.1016/j.bmcl.2011.03.067
  • Primary Citation of Related Structures:  
    3Q0Z

  • PubMed Abstract: 

    Herein, we present initial SAR studies on a series of bridged 2-arylindole-based NS5B inhibitors. The introduction of bridging elements between the indole N1 and the ortho-position of the 2-aryl moiety resulted in conformationally constrained heterocycles that possess multiple additional vectors for further exploration. The binding mode and pharmacokinetic (PK) properties of select examples, including: 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-d][1,4]benzodiazepine-10-carboxylic acid (7) (IC(50)=0.07 μM, %F=18), are reported.


  • Organizational Affiliation

    Discovery Chemistry and Candidate Optimization, Bristol Myers Squibb, Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. xiaofan.zheng@bms.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase
A, B
574Hepatitis C virus subtype 1bMutation(s): 0 
Gene Names: NS5B
EC: 2.7.7.48
UniProt
Find proteins for Q9WMX2 (Hepatitis C virus genotype 1b (isolate Con1))
Explore Q9WMX2 
Go to UniProtKB:  Q9WMX2
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9WMX2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
23E
Query on 23E

Download Ideal Coordinates CCD File 
C [auth A],
I [auth B]
(2E)-3-(4-{[(1-{[(13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepin-10-yl)carbonyl]amino}cyclopentyl)carbonyl]amino}phenyl)prop-2-enoic acid
C38 H38 N4 O5
HDBNVTWMHMMKNY-XMHGGMMESA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A]
E [auth A]
F [auth A]
G [auth A]
H [auth A]
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
J [auth B],
K [auth B],
L [auth B],
M [auth B],
N [auth B]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
23E PDBBind:  3Q0Z IC50: 20 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.29 Å
  • R-Value Free: 0.224 
  • R-Value Work: 0.200 
  • R-Value Observed: 0.201 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 66.3α = 90
b = 91.4β = 90
c = 231.7γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Released Date: 2011-04-27 
  • Deposition Author(s): Sheriff, S.

Revision History  (Full details and data files)

  • Version 1.0: 2011-04-27
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2023-09-13
    Changes: Data collection, Database references, Derived calculations, Refinement description