3ARA

Discovery of Novel Uracil Derivatives as Potent Human dUTPase Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.215 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Synthesis and discovery of N-carbonylpyrrolidine- or N-sulfonylpyrrolidine-containing uracil derivatives as potent human deoxyuridine triphosphatase inhibitors

Miyakoshi, H.Miyahara, S.Yokogawa, T.Chong, K.T.Taguchi, J.Endoh, K.Yano, W.Wakasa, T.Ueno, H.Takao, Y.Nomura, M.Shuto, S.Nagasawa, H.Fukuoka, M.

(2012) J Med Chem 55: 2960-2969

  • DOI: https://doi.org/10.1021/jm201627n
  • Primary Citation of Related Structures:  
    3ARA

  • PubMed Abstract: 

    Recently, deoxyuridine triphosphatase (dUTPase) has emerged as a potential target for drug development as part of a new strategy of 5-fluorouracil-based combination chemotherapy. We have initiated a program to develop potent drug-like dUTPase inhibitors based on structure-activity relationship (SAR) studies of uracil derivatives. N-Carbonylpyrrolidine- and N-sulfonylpyrrolidine-containing uracils were found to be promising scaffolds that led us to human dUTPase inhibitors (12k) having excellent potencies (IC(50) = 0.15 μM). The X-ray structure of a complex of 16a and human dUTPase revealed a unique binding mode wherein its uracil ring and phenyl ring occupy a uracil recognition region and a hydrophobic region, respectively, and are stacked on each other. Compounds 12a and 16a markedly enhanced the growth inhibition activity of 5-fluoro-2'-deoxyuridine against HeLa S3 cells in vitro (EC(50) = 0.27-0.30 μM), suggesting that our novel dUTPase inhibitors could contribute to the development of chemotherapeutic strategies when used in combination with TS inhibitors.


  • Organizational Affiliation

    Drug Discovery Research Center, Taiho Pharmaceutical Co. Ltd., Okubo 3, Tsukuba, Ibaraki 300-2611, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Deoxyuridine 5'-triphosphate nucleotidohydrolase
A, B, C
164Homo sapiensMutation(s): 0 
EC: 3.6.1.23
UniProt & NIH Common Fund Data Resources
Find proteins for P33316 (Homo sapiens)
Explore P33316 
Go to UniProtKB:  P33316
PHAROS:  P33316
GTEx:  ENSG00000128951 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP33316
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
MKH BindingDB:  3ARA IC50: min: 320, max: 480 (nM) from 2 assay(s)
Binding MOAD:  3ARA IC50: 320 (nM) from 1 assay(s)
PDBBind:  3ARA IC50: 320 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.214 
  • R-Value Observed: 0.215 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 81.89α = 90
b = 83.263β = 90
c = 89.662γ = 90
Software Package:
Software NamePurpose
AMoREphasing
REFMACrefinement
CrystalCleardata reduction
CrystalCleardata 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: 2010-12-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-05-30
    Changes: Database references
  • Version 1.3: 2017-10-11
    Changes: Refinement description
  • Version 1.4: 2024-03-13
    Changes: Data collection, Database references, Derived calculations