6BQK

CRYSTAL STRUCTURE OF HEPATIS C VIRUS PROTEASE (NS3) COMPLEXED WITH TRIPEPTIDIC ACYL SULFONAMIDE INHIBITOR (COMPOUND 18)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.254 
  • R-Value Observed: 0.254 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor.

Zheng, B.D'Andrea, S.V.Sun, L.Q.Wang, A.X.Chen, Y.Hrnciar, P.Friborg, J.Falk, P.Hernandez, D.Yu, F.Sheaffer, A.K.Knipe, J.O.Mosure, K.Rajamani, R.Good, A.C.Kish, K.Tredup, J.Klei, H.E.Paruchuri, M.Ng, A.Gao, Q.Rampulla, R.A.Mathur, A.Meanwell, N.A.McPhee, F.Scola, P.M.

(2018) ACS Med Chem Lett 9: 143-148

  • DOI: https://doi.org/10.1021/acsmedchemlett.7b00503
  • Primary Citation of Related Structures:  
    6BQJ, 6BQK

  • PubMed Abstract: 

    The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of 18 with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C-H of the CHF 2 moiety and the backbone carbonyl of Leu135 of the enzyme. Structure-activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH 3 and CF 3 analogues, respectively, providing insight into the deployment of this unique amino acid.


  • Organizational Affiliation

    Research and Development, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, Connecticut 06492, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
NS3 protease
A, B
219Hepacivirus hominisMutation(s): 0 
UniProt
Find proteins for P27958 (Hepatitis C virus genotype 1a (isolate H77))
Explore P27958 
Go to UniProtKB:  P27958
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP27958
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Z1E
Query on Z1E

Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]
N-(tert-butoxycarbonyl)-3-methyl-L-valyl-(4R)-4-[(7-chloro-4-methoxyisoquinolin-1-yl)oxy]-N-[(1R,2R)-1-[(cyclopropylsulfonyl)carbamoyl]-2-(difluoromethyl)cyclopropyl]-L-prolinamide
C34 H44 Cl F2 N5 O9 S
PSVSXONHXYMVQH-GGFAASIMSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
Z1E Binding MOAD:  6BQK IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.97 Å
  • R-Value Free: 0.267 
  • R-Value Work: 0.254 
  • R-Value Observed: 0.254 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.65α = 90
b = 68.06β = 109.58
c = 61.46γ = 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: 2018-03-21
    Type: Initial release
  • Version 1.1: 2024-03-13
    Changes: Data collection, Database references