6JME

Crystal structure of human DHODH in complex with inhibitor 0946


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.170 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.149 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Bifunctional Naphtho[2,3- d ][1,2,3]triazole-4,9-dione Compounds Exhibit Antitumor Effects In Vitro and In Vivo by Inhibiting Dihydroorotate Dehydrogenase and Inducing Reactive Oxygen Species Production.

Zuo, Z.Liu, X.Qian, X.Zeng, T.Sang, N.Liu, H.Zhou, Y.Tao, L.Zhou, X.Su, N.Yu, Y.Chen, Q.Luo, Y.Zhao, Y.

(2020) J Med Chem 63: 7633-7652

  • DOI: https://doi.org/10.1021/acs.jmedchem.0c00512
  • Primary Citation of Related Structures:  
    6JMD, 6JME, 6LP6, 6LP7, 6LP8

  • PubMed Abstract: 

    Human dihydroorotate dehydrogenase ( h DHODH) is an attractive target for cancer therapy. Based on its crystal structure, we designed and synthesized a focused compound library containing the structural moiety of 1,4-benzoquinone, which possesses reactive oxygen species (ROS) induction capacity. Compound 3s with a naphtho[2,3- d ][1,2,3]triazole-4,9-dione scaffold exhibited inhibitory activity against h DHODH. Further optimization led to compounds 11k and 11l , which inhibited h DHODH activity with IC 50 values of 9 and 4.5 nM, respectively. Protein-ligand cocrystal structures clearly depicted hydrogen bond and hydrophobic interactions of 11k and 11l with h DHODH. Compounds 11k and 11l significantly inhibited leukemia cell and solid tumor cell proliferation and induced ROS production, mitochondrial dysfunction, apoptosis, and cell cycle arrest. Nanocrystallization of compound 11l displayed significant in vivo antitumor effects in the Raji xenograft model. Overall, this study provides a novel bifunctional compound 11l with h DHODH inhibition and ROS induction efficacy, which represents a promising anticancer lead worthy of further exploration.


  • Organizational Affiliation

    State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydroorotate dehydrogenase (quinone), mitochondrial366Homo sapiensMutation(s): 0 
Gene Names: DHODH
EC: 1.3.5.2
UniProt & NIH Common Fund Data Resources
Find proteins for Q02127 (Homo sapiens)
Explore Q02127 
Go to UniProtKB:  Q02127
PHAROS:  Q02127
GTEx:  ENSG00000102967 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ02127
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
FMN
Query on FMN

Download Ideal Coordinates CCD File 
B [auth A]FLAVIN MONONUCLEOTIDE
C17 H21 N4 O9 P
FVTCRASFADXXNN-SCRDCRAPSA-N
BVU (Subject of Investigation/LOI)
Query on BVU

Download Ideal Coordinates CCD File 
J [auth A]3-[3,5-bis(fluoranyl)-4-(2-fluorophenyl)phenyl]benzo[f]benzotriazole-4,9-dione
C22 H10 F3 N3 O2
VMUZFSZBQDZDTG-UHFFFAOYSA-N
LDA
Query on LDA

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

Download Ideal Coordinates CCD File 
C [auth A]OROTIC ACID
C5 H4 N2 O4
PXQPEWDEAKTCGB-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
D [auth A],
E [auth A],
K [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
ACT
Query on ACT

Download Ideal Coordinates CCD File 
F [auth A],
G [auth A],
H [auth A]
ACETATE ION
C2 H3 O2
QTBSBXVTEAMEQO-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
L [auth A],
M [auth A],
N [auth A]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
BVU BindingDB:  6JME IC50: 4.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.170 
  • R-Value Work: 0.148 
  • R-Value Observed: 0.149 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.605α = 90
b = 90.605β = 90
c = 123.057γ = 120
Software Package:
Software NamePurpose
PHENIXrefinement
HKL-3000data reduction
HKL-3000data scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2020-03-18
    Type: Initial release
  • Version 1.1: 2020-09-30
    Changes: Database references, Derived calculations
  • Version 1.2: 2024-03-27
    Changes: Data collection, Database references