6FMD

Targeting myeloid differentiation using potent human dihydroorotate dehydrogenase (hDHODH) inhibitors based on 2-hydroxypyrazolo[1,5-a]pyridine scaffold


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.160 
  • R-Value Work: 0.137 
  • R-Value Observed: 0.138 

Starting Model: experimental
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wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Targeting Myeloid Differentiation Using Potent 2-Hydroxypyrazolo[1,5- a]pyridine Scaffold-Based Human Dihydroorotate Dehydrogenase Inhibitors.

Sainas, S.Pippione, A.C.Lupino, E.Giorgis, M.Circosta, P.Gaidano, V.Goyal, P.Bonanni, D.Rolando, B.Cignetti, A.Ducime, A.Andersson, M.Jarva, M.Friemann, R.Piccinini, M.Ramondetti, C.Buccinna, B.Al-Karadaghi, S.Boschi, D.Saglio, G.Lolli, M.L.

(2018) J Med Chem 61: 6034-6055

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00373
  • Primary Citation of Related Structures:  
    6FMD

  • PubMed Abstract: 

    Human dihydroorotate dehydrogenase ( hDHODH) catalyzes the rate-limiting step in de novo pyrimidine biosynthesis, the conversion of dihydroorotate to orotate. hDHODH has recently been found to be associated with acute myelogenous leukemia, a disease for which the standard of intensive care has not changed over decades. This work presents a novel class of hDHODH inhibitors, which are based on an unusual carboxylic group bioisostere 2-hydroxypyrazolo[1,5- a]pyridine, that has been designed starting from brequinar, one of the most potent hDHODH inhibitors. A combination of structure-based and ligand-based strategies produced compound 4, which shows brequinar-like hDHODH potency in vitro and is superior in terms of cytotoxicity and immunosuppression. Compound 4 also restores myeloid differentiation in leukemia cell lines at concentrations that are one log digit lower than those achieved in experiments with brequinar. This Article reports the design, synthesis, SAR, X-ray crystallography, biological assays, and physicochemical characterization of the new class of hDHODH inhibitors.


  • Organizational Affiliation

    Department of Molecular Biotechnology and Health Sciences , University of Turin , Turin 10126 , Italy.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Dihydroorotate dehydrogenase (quinone), mitochondrial395Homo 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 
E [auth A]FLAVIN MONONUCLEOTIDE
C17 H21 N4 O9 P
FVTCRASFADXXNN-SCRDCRAPSA-N
DUH (Subject of Investigation/LOI)
Query on DUH

Download Ideal Coordinates CCD File 
B [auth A]2-oxidanyl-~{N}-[2,3,5,6-tetrakis(fluoranyl)-4-phenyl-phenyl]pyrazolo[1,5-a]pyridine-3-carboxamide
C20 H11 F4 N3 O2
JIIXZPWFDKPNKW-UHFFFAOYSA-N
ORO
Query on ORO

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

Download Ideal Coordinates CCD File 
Q [auth A]
R [auth A]
S [auth A]
T [auth A]
U [auth A]
Q [auth A],
R [auth A],
S [auth A],
T [auth A],
U [auth A],
V [auth A]
TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
M [auth A],
N [auth A],
O [auth A],
P [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
ACT
Query on ACT

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

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
DUH BindingDB:  6FMD IC50: 1.2 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.58 Å
  • R-Value Free: 0.160 
  • R-Value Work: 0.137 
  • R-Value Observed: 0.138 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 90.441α = 90
b = 90.441β = 90
c = 122.446γ = 120
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
PDB_EXTRACTdata extraction

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
MAX4ESSFUNSwedenGU-003

Revision History  (Full details and data files)

  • Version 1.0: 2018-07-11
    Type: Initial release
  • Version 1.1: 2018-07-18
    Changes: Data collection, Database references
  • Version 1.2: 2018-08-08
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Data collection, Database references, Refinement description