4NLD

Crystal structure of the hepatitis C virus NS5B RNA-dependent RNA polymerase complex with BMS-791325 also known as (1aR,12bS)-8-cyclohexyl-n-(dimethylsulfamoyl)-11-methoxy-1a-{[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide and 2-(4-fluorophenyl)-n-methyl-6-[(methylsulfonyl)amino]-5-(propan-2-yloxy)-1-benzofuran-3-carboxamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Discovery and Preclinical Characterization of the Cyclopropylindolobenzazepine BMS-791325, A Potent Allosteric Inhibitor of the Hepatitis C Virus NS5B Polymerase.

Gentles, R.G.Ding, M.Bender, J.A.Bergstrom, C.P.Grant-Young, K.Hewawasam, P.Hudyma, T.Martin, S.Nickel, A.Regueiro-Ren, A.Tu, Y.Yang, Z.Yeung, K.S.Zheng, X.Chao, S.Sun, J.H.Beno, B.R.Camac, D.M.Chang, C.H.Gao, M.Morin, P.E.Sheriff, S.Tredup, J.Wan, J.Witmer, M.R.Xie, D.Hanumegowda, U.Knipe, J.Mosure, K.Santone, K.S.Parker, D.D.Zhuo, X.Lemm, J.Liu, M.Pelosi, L.Rigat, K.Voss, S.Wang, Y.Wang, Y.K.Colonno, R.J.Gao, M.Roberts, S.B.Gao, Q.Ng, A.Meanwell, N.A.Kadow, J.F.

(2014) J Med Chem 57: 1855-1879

  • DOI: https://doi.org/10.1021/jm4016894
  • Primary Citation of Related Structures:  
    4NLD

  • PubMed Abstract: 

    Described herein are structure-activity relationship studies that resulted in the optimization of the activity of members of a class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors. Subsequent iterations of analogue design and syntheses successfully addressed off-target activities, most notably human pregnane X receptor (hPXR) transactivation, and led to significant improvements in the physicochemical properties of lead compounds. Those analogues exhibiting improved solubility and membrane permeability were shown to have notably enhanced pharmacokinetic profiles. Additionally, a series of alkyl bridged piperazine carboxamides was identified as being of particular interest, and from which the compound BMS-791325 (2) was found to have distinguishing antiviral, safety, and pharmacokinetic properties that resulted in its selection for clinical evaluation.


  • Organizational Affiliation

    Discovery Chemistry, ‡Molecular Discovery Technologies, Molecular Structure & Design, §Molecular Discovery Technologies, Protein Science, ∥Pharmaceutical Candidate Optimization, ⊥Discovery Virology, Disease Sciences and Biologics, #Leads Discovery and Optimization, ▽Materials Science, Drug Product Science and Technology, Bristol-Myers Squibb Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
RNA-directed RNA polymerase574Hepatitis C virus (isolate Con1)Mutation(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 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2N7
Query on 2N7

Download Ideal Coordinates CCD File 
B [auth A](1aR,12bS)-8-cyclohexyl-N-(dimethylsulfamoyl)-11-methoxy-1a-{[(1R,5S)-3-methyl-3,8-diazabicyclo[3.2.1]oct-8-yl]carbonyl}-1,1a,2,12b-tetrahydrocyclopropa[d]indolo[2,1-a][2]benzazepine-5-carboxamide
C36 H45 N5 O5 S
ZTTKEBYSXUCBSE-QDFUAKMASA-N
2N5
Query on 2N5

Download Ideal Coordinates CCD File 
C [auth A]2-(4-fluorophenyl)-N-methyl-6-[(methylsulfonyl)amino]-5-(propan-2-yloxy)-1-benzofuran-3-carboxamide
C20 H21 F N2 O5 S
VBRUONUESYTIDA-UHFFFAOYSA-N
BOG
Query on BOG

Download Ideal Coordinates CCD File 
H [auth A],
I [auth A]
octyl beta-D-glucopyranoside
C14 H28 O6
HEGSGKPQLMEBJL-RKQHYHRCSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
F [auth A],
G [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.75 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.213 
  • R-Value Observed: 0.215 
  • Space Group: I 2 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73α = 90
b = 120.6β = 90
c = 201.5γ = 90
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data scaling
AMoREphasing
BUSTERrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2014-03-19 
  • Deposition Author(s): Sheriff, S.

Revision History  (Full details and data files)

  • Version 1.0: 2014-03-19
    Type: Initial release
  • Version 1.1: 2014-03-26
    Changes: Database references
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Database references, Derived calculations, Structure summary
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Structure summary