3JSU

Quadruple mutant(N51I+C59R+S108N+I164L) plasmodium falciparum dihydrofolate reductase-thymidylate synthase(PFDHFR-TS) complexed with QN254, NADPH, and dUMP


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.206 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Preclinical evaluation of the antifolate QN254, 5-chloro- N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine, as an antimalarial drug candidate

Nzila, A.Rottmann, M.Chitnumsub, P.Kiara, S.M.Kamchonwongpaisan, S.Maneeruttanarungroj, C.Taweechai, S.Yeung, B.K.Goh, A.Lakshminarayana, S.B.Zou, B.Wong, J.Ma, N.L.Weaver, M.Keller, T.H.Dartois, V.Wittlin, S.Brun, R.Yuthavong, Y.Diagana, T.T.

(2010) Antimicrob Agents Chemother 54: 2603-2610

  • DOI: https://doi.org/10.1128/AAC.01526-09
  • Primary Citation of Related Structures:  
    3JSU

  • PubMed Abstract: 

    Drug resistance against dihydrofolate reductase (DHFR) inhibitors-such as pyrimethamine (PM)-has now spread to almost all regions where malaria is endemic, rendering antifolate-based malaria treatments highly ineffective. We have previously shown that the di-amino quinazoline QN254 [5-chloro-N'6'-(2,5-dimethoxy-benzyl)-quinazoline-2,4,6-triamine] is active against the highly PM-resistant Plasmodium falciparum V1S strain, suggesting that QN254 could be used to treat malaria in regions with a high prevalence of antifolate resistance. Here, we further demonstrate that QN254 is highly active against Plasmodium falciparum clinical isolates, displaying various levels of antifolate drug resistance, and we provide biochemical and structural evidence that QN254 binds and inhibits the function of both the wild-type and the quadruple-mutant (V1S) forms of the DHFR enzyme. In addition, we have assessed QN254 oral bioavailability, efficacy, and safety in vivo. The compound displays favorable pharmacokinetic properties after oral administration in rodents. The drug was remarkably efficacious against Plasmodium berghei and could fully cure infected mice with three daily oral doses of 30 mg/kg. In the course of these efficacy studies, we have uncovered some dose limiting toxicity at higher doses that was confirmed in rats. Thus, despite its relative in vitro selectivity toward the Plasmodium DHFR enzyme, QN254 does not show the adequate therapeutic index to justify its further development as a single agent.


  • Organizational Affiliation

    Kenya Medical Research Institute/Wellcome Trust Collaborative Research Program, Kilifi, Kenya.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydrofolate reductase-thymidylate synthase
A, B
608Plasmodium falciparumMutation(s): 4 
Gene Names: DHFR-TSV1/S
EC: 1.5.1.3 (PDB Primary Data), 2.1.1.45 (PDB Primary Data)
UniProt
Find proteins for D9N170 (Plasmodium falciparum)
Explore D9N170 
Go to UniProtKB:  D9N170
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupD9N170
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
KA5 BindingDB:  3JSU IC50: 0.39 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.70 Å
  • R-Value Free: 0.233 
  • R-Value Work: 0.206 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.991α = 90
b = 157.375β = 90
c = 165.511γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
PDB_EXTRACTdata extraction
superguidata collection
HKL-2000data reduction
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-07-28
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-11-01
    Changes: Refinement description
  • Version 1.3: 2023-11-01
    Changes: Data collection, Database references, Derived calculations, Refinement description