3SDG

Ethionamide Boosters Part 2: Combining Bioisosteric Replacement and Structure-Based Drug Design to Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors.

Flipo, M.Desroses, M.Lecat-Guillet, N.Villemagne, B.Blondiaux, N.Leroux, F.Piveteau, C.Mathys, V.Flament, M.P.Siepmann, J.Villeret, V.Wohlkonig, A.Wintjens, R.Soror, S.H.Christophe, T.Jeon, H.K.Locht, C.Brodin, P.Deprez, B.Baulard, A.R.Willand, N.

(2012) J Med Chem 55: 68-83

  • DOI: https://doi.org/10.1021/jm200825u
  • Primary Citation of Related Structures:  
    3SDG, 3SFI

  • PubMed Abstract: 

    Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore, a second phase of optimization was required. Herein a structure-property relationship study is reported according to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration.


  • Organizational Affiliation

    Université Lille Nord de France, F-59000 Lille, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
HTH-type transcriptional regulator EthR236Mycobacterium tuberculosis H37RvMutation(s): 0 
Gene Names: etaRethRMT3970Rv3855
UniProt
Find proteins for P9WMC1 (Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv))
Explore P9WMC1 
Go to UniProtKB:  P9WMC1
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP9WMC1
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
3SE
Query on 3SE

Download Ideal Coordinates CCD File 
B [auth A]4,4,4-trifluoro-1-{4-[3-(1,3-thiazol-2-yl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl}butan-1-one
C14 H15 F3 N4 O2 S
HHWOKDABGQJATF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3SE PDBBind:  3SDG IC50: 2800 (nM) from 1 assay(s)
BindingDB:  3SDG IC50: 2800 (nM) from 1 assay(s)
EC50: 500 (nM) from 1 assay(s)
Binding MOAD:  3SDG IC50: 2800 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.87 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.203 
  • R-Value Observed: 0.205 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.82α = 90
b = 121.82β = 90
c = 33.61γ = 90
Software Package:
Software NamePurpose
XDSdata scaling
MOLREPphasing
REFMACrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2011-12-07
    Type: Initial release
  • Version 1.1: 2012-01-25
    Changes: Database references
  • Version 1.2: 2018-01-24
    Changes: Structure summary
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations