5TBO

Crystal structure of Plasmodium falciparum dihydroorotate dehydrogenase bound with Inhibitor DSM421


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.6 of the entry. See complete history


Literature

A Triazolopyrimidine-Based Dihydroorotate Dehydrogenase Inhibitor with Improved Drug-like Properties for Treatment and Prevention of Malaria.

Phillips, M.A.White, K.L.Kokkonda, S.Deng, X.White, J.El Mazouni, F.Marsh, K.Tomchick, D.R.Manjalanagara, K.Rudra, K.R.Wirjanata, G.Noviyanti, R.Price, R.N.Marfurt, J.Shackleford, D.M.Chiu, F.C.Campbell, M.Jimenez-Diaz, M.B.Bazaga, S.F.Angulo-Barturen, I.Martinez, M.S.Lafuente-Monasterio, M.Kaminsky, W.Silue, K.Zeeman, A.M.Kocken, C.Leroy, D.Blasco, B.Rossignol, E.Rueckle, T.Matthews, D.Burrows, J.N.Waterson, D.Palmer, M.J.Rathod, P.K.Charman, S.A.

(2016) ACS Infect Dis 2: 945-957

  • DOI: https://doi.org/10.1021/acsinfecdis.6b00144
  • Primary Citation of Related Structures:  
    5TBO

  • PubMed Abstract: 

    The emergence of drug-resistant malaria parasites continues to hamper efforts to control this lethal disease. Dihydroorotate dehydrogenase has recently been validated as a new target for the treatment of malaria, and a selective inhibitor (DSM265) of the Plasmodium enzyme is currently in clinical development. With the goal of identifying a backup compound to DSM265, we explored replacement of the SF 5 -aniline moiety of DSM265 with a series of CF 3 -pyridinyls while maintaining the core triazolopyrimidine scaffold. This effort led to the identification of DSM421, which has improved solubility, lower intrinsic clearance, and increased plasma exposure after oral dosing compared to DSM265, while maintaining a long predicted human half-life. Its improved physical and chemical properties will allow it to be formulated more readily than DSM265. DSM421 showed excellent efficacy in the SCID mouse model of P. falciparum malaria that supports the prediction of a low human dose (<200 mg). Importantly DSM421 showed equal activity against both P. falciparum and P. vivax field isolates, while DSM265 was more active on P. falciparum. DSM421 has the potential to be developed as a single-dose cure or once-weekly chemopreventative for both P. falciparum and P. vivax malaria, leading to its advancement as a preclinical development candidate.


  • Organizational Affiliation

    Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University , Parkville, VIC 3052, Australia.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydroorotate dehydrogenase (quinone), mitochondrial401Plasmodium falciparum 3D7Mutation(s): 0 
Gene Names: PFF0160c
EC: 1.3.5.2
UniProt
Find proteins for Q08210 (Plasmodium falciparum (isolate 3D7))
Explore Q08210 
Go to UniProtKB:  Q08210
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ08210
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FMN
Query on FMN

Download Ideal Coordinates CCD File 
C [auth A]FLAVIN MONONUCLEOTIDE
C17 H21 N4 O9 P
FVTCRASFADXXNN-SCRDCRAPSA-N
78Z
Query on 78Z

Download Ideal Coordinates CCD File 
B [auth A]2-(1,1-difluoroethyl)-5-methyl-N-[6-(trifluoromethyl)pyridin-3-yl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine
C14 H11 F5 N6
HDLFZCDEGAWEFX-UHFFFAOYSA-N
LDA
Query on LDA

Download Ideal Coordinates CCD File 
E [auth A]LAURYL DIMETHYLAMINE-N-OXIDE
C14 H31 N O
SYELZBGXAIXKHU-UHFFFAOYSA-N
ORO
Query on ORO

Download Ideal Coordinates CCD File 
D [auth A]OROTIC ACID
C5 H4 N2 O4
PXQPEWDEAKTCGB-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.15 Å
  • R-Value Free: 0.219 
  • R-Value Work: 0.181 
  • R-Value Observed: 0.183 
  • Space Group: P 64
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.38α = 90
b = 86.38β = 90
c = 138.608γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)United States--

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-28
    Type: Initial release
  • Version 1.1: 2016-10-12
    Changes: Database references
  • Version 1.2: 2016-12-21
    Changes: Database references
  • Version 1.3: 2017-09-20
    Changes: Author supporting evidence
  • Version 1.4: 2019-12-25
    Changes: Author supporting evidence
  • Version 1.5: 2020-10-21
    Changes: Data collection
  • Version 1.6: 2023-10-04
    Changes: Data collection, Database references, Refinement description