4KTC

NS3/NS4A protease with inhibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Danoprevir (ITMN-191/R7227), a Highly Selective and Potent Inhibitor of Hepatitis C Virus (HCV) NS3/4A Protease.

Jiang, Y.Andrews, S.W.Condroski, K.R.Buckman, B.Serebryany, V.Wenglowsky, S.Kennedy, A.L.Madduru, M.R.Wang, B.Lyon, M.Doherty, G.A.Woodard, B.T.Lemieux, C.Do, M.G.Zhang, H.Ballard, J.Vigers, G.Brandhuber, B.J.Stengel, P.Josey, J.A.Beigelman, L.Blatt, L.Seiwert, S.D.

(2014) J Med Chem 57: 1753-1769

  • DOI: https://doi.org/10.1021/jm400164c
  • Primary Citation of Related Structures:  
    4KTC

  • PubMed Abstract: 

    HCV serine protease NS3 represents an attractive drug target because it is not only essential for viral replication but also implicated in the viral evasion of the host immune response pathway through direct cleavage of key proteins in the human innate immune system. Through structure-based drug design and optimization, macrocyclic peptidomimetic molecules bearing both a lipophilic P2 isoindoline carbamate and a P1/P1' acylsulfonamide/acylsulfamide carboxylic acid bioisostere were prepared that possessed subnanomolar potency against the NS3 protease in a subgenomic replicon-based cellular assay (Huh-7). Danoprevir (compound 49) was selected as the clinical development candidate for its favorable potency profile across multiple HCV genotypes and key mutant strains and for its good in vitro ADME profiles and in vivo target tissue (liver) exposures across multiple animal species. X-ray crystallographic studies elucidated several key features in the binding of danoprevir to HCV NS3 protease and proved invaluable to our iterative structure-based design strategy.


  • Organizational Affiliation

    Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Serine protease NS3
A, C
190Hepatitis C virus (isolate Japanese)Mutation(s): 2 
EC: 3.4.21.98 (PDB Primary Data), 3.6.1.15 (PDB Primary Data), 3.6.4.13 (PDB Primary Data)
UniProt
Find proteins for P26662 (Hepatitis C virus genotype 1b (isolate Japanese))
Explore P26662 
Go to UniProtKB:  P26662
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP26662
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
NS4A peptide
B, D
16synthetic constructMutation(s): 0 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1X3
Query on 1X3

Download Ideal Coordinates CCD File 
F [auth A],
H [auth C]
(2R,6S,13aR,14aR,16aS)-6-{[(cyclopentyloxy)carbonyl]amino}-14a-[(cyclopropylsulfonyl)carbamoyl]-5,16-dioxooctadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-2-yl 3,4-dihydroisoquinoline-2(1H)-carboxylate
C37 H51 N5 O9 S
VQZYSHWAKCNHJX-IVYVMHIUSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
G [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1X3 Binding MOAD:  4KTC IC50: 1 (nM) from 1 assay(s)
PDBBind:  4KTC IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.258 
  • R-Value Work: 0.206 
  • R-Value Observed: 0.209 
  • Space Group: P 63
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.988α = 90
b = 72.988β = 90
c = 127.48γ = 120
Software Package:
Software NamePurpose
CrystalCleardata collection
MLPHAREphasing
REFMACrefinement
CrystalCleardata reduction
SCALAdata 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: 2013-08-07
    Type: Initial release
  • Version 1.1: 2014-03-26
    Changes: Database references
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description