3T70

5'-Diphenyl Nucleoside Inhibitors of Plasmodium falciparum dUTPase


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Design, synthesis, and evaluation of 5'-diphenyl nucleoside analogues as inhibitors of the Plasmodium falciparum dUTPase.

Hampton, S.E.Baragana, B.Schipani, A.Bosch-Navarrete, C.Musso-Buendia, J.A.Recio, E.Kaiser, M.Whittingham, J.L.Roberts, S.M.Shevtsov, M.Brannigan, J.A.Kahnberg, P.Brun, R.Wilson, K.S.Gonzalez-Pacanowska, D.Johansson, N.G.Gilbert, I.H.

(2011) ChemMedChem 6: 1816-1831

  • DOI: https://doi.org/10.1002/cmdc.201100255
  • Primary Citation of Related Structures:  
    3T60, 3T64, 3T6Y, 3T70

  • PubMed Abstract: 

    Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase) is a potential drug target for malaria. We previously reported some 5'-tritylated deoxyuridine analogues (both cyclic and acyclic) as selective inhibitors of the Plasmodium falciparum dUTPase. Modelling studies indicated that it might be possible to replace the trityl group with a diphenyl moiety, as two of the phenyl groups are buried, whereas the third is exposed to solvent. Herein we report the synthesis and evaluation of some diphenyl analogues that have lower lipophilicity and molecular weight than the trityl lead compound. Co-crystal structures show that the diphenyl inhibitors bind in a similar manner to the corresponding trityl derivatives, with the two phenyl moieties occupying the predicted buried phenyl binding sites. The diphenyl compounds prepared show similar or slightly lower inhibition of PfdUTPase, and similar or weaker inhibition of parasite growth than the trityl compounds.


  • Organizational Affiliation

    Division of Biological Chemistry and Drug Discovery, College of Life Science, University of Dundee, Sir James Black Centre, Dundee DD1 5EH, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Deoxyuridine 5'-triphosphate nucleotidohydrolase, putative
A, B, C
181Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PF11_0282
EC: 3.6.1.23
UniProt
Find proteins for Q8II92 (Plasmodium falciparum (isolate 3D7))
Explore Q8II92 
Go to UniProtKB:  Q8II92
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ8II92
Sequence Annotations
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  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
PEPTIDE GLY-HIS-GLYD [auth F]3synthetic constructMutation(s): 0 
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DU4
Query on DU4

Download Ideal Coordinates CCD File 
E [auth A],
G [auth B],
K [auth C]
2',5'-dideoxy-5'-[(diphenylmethyl)(methyl)amino]uridine
C23 H25 N3 O4
GMULPQZINUAVEX-QKNQBKEWSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A]
H [auth B]
I [auth B]
J [auth B]
L [auth C]
F [auth A],
H [auth B],
I [auth B],
J [auth B],
L [auth C],
M [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Binding Affinity Annotations 
IDSourceBinding Affinity
DU4 PDBBind:  3T70 Ki: 500 (nM) from 1 assay(s)
Binding MOAD:  3T70 Ki: 500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.232 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 
  • Space Group: P 41
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 76.75α = 90
b = 76.75β = 90
c = 105.83γ = 90
Software Package:
Software NamePurpose
ADSCdata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-08-29
    Type: Initial release
  • Version 1.1: 2019-10-09
    Changes: Advisory, Data collection, Database references, Source and taxonomy
  • Version 1.2: 2023-11-01
    Changes: Advisory, Data collection, Database references, Derived calculations, Refinement description