4MOT

Structure of Streptococcus pneumonia pare in complex with AZ13072886

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 

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Literature

Thiazolopyridone ureas as DNA gyrase B inhibitors: Optimization of antitubercular activity and efficacy.

Kale, R.R., Kale, M.G., Waterson, D., Raichurkar, A., Hameed, S.P., Manjunatha, M.R., Kishore Reddy, B.K., Malolanarasimhan, K., Shinde, V., Koushik, K., Jena, L.K., Menasinakai, S., Humnabadkar, V., Madhavapeddi, P., Basavarajappa, H., Sharma, S., Nandishaiah, R., Mahesh Kumar, K.N., Ganguly, S., Ahuja, V., Gaonkar, S., Naveen Kumar, C.N., Ogg, D., Boriack-Sjodin, P.A., Sambandamurthy, V.K., de Sousa, S.M., Ghorpade, S.R.

(2014) Bioorg Med Chem Lett 24: 870-879

  • DOI: https://doi.org/10.1016/j.bmcl.2013.12.080
  • Primary Citation of Related Structures:  
    4MOT

  • PubMed Abstract: 

    Scaffold hopping from the thiazolopyridine ureas led to thiazolopyridone ureas with potent antitubercular activity acting through inhibition of DNA GyrB ATPase activity. Structural diversity was introduced, by extension of substituents from the thiazolopyridone N-4 position, to access hydrophobic interactions in the ribose pocket of the ATP binding region of GyrB. Further optimization of hydrogen bond interactions with arginines in site-2 of GyrB active site pocket led to potent inhibition of the enzyme (IC50 2 nM) along with potent cellular activity (MIC=0.1 μM) against Mycobacterium tuberculosis (Mtb). Efficacy was demonstrated in an acute mouse model of tuberculosis on oral administration.

    • Organizational Affiliation: 

    Department of Medicinal Chemistry, AstraZeneca India Pvt. Ltd, Bellary Road, Hebbal, Bangalore 560024, India.


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Topoisomerase IV subunit B226Streptococcus pneumoniae R6Mutation(s): 0 
Gene Names: parE, spar94_0831, spr0756
EC: 5.99.1
UniProt
Find proteins for Q8DQB5 (Streptococcus pneumoniae (strain ATCC BAA-255 / R6))
Explore Q8DQB5 
Go to UniProtKB:  Q8DQB5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8DQB5
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2B7
Query on 2B7
Download Ideal Coordinates CCD File 
B [auth A]1-[4-(3-methylbutyl)-5-oxo-6-(pyridin-3-yl)-4,5-dihydro[1,3]thiazolo[5,4-b]pyridin-2-yl]-3-prop-2-en-1-ylurea
C20 H23 N5 O2 S
HDSYKPYXRVXIRI-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2B7 PDBBind:  4MOT IC50: 50 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.75 Å
  • R-Value Free: 0.228 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 73.603α = 90
b = 94.571β = 90
c = 61.001γ = 90
Software Package:
Software NamePurpose
StructureStudiodata collection
AMoREphasing
REFMACrefinement
d*TREKdata reduction
d*TREKdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2013-11-20
    Type: Initial release
  • Version 1.1: 2013-11-27
    Changes: Data collection
  • Version 1.2: 2014-02-12
    Changes: Database references
  • Version 1.3: 2018-01-24
    Changes: Structure summary
  • Version 1.4: 2024-02-28
    Changes: Data collection, Database references, Derived calculations