5W8L

Crystal Structure of Lactate Dehydrogenase A in complex with inhibitor compound 59 and NADH


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.147 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery and Optimization of Potent, Cell-Active Pyrazole-Based Inhibitors of Lactate Dehydrogenase (LDH).

Rai, G.Brimacombe, K.R.Mott, B.T.Urban, D.J.Hu, X.Yang, S.M.Lee, T.D.Cheff, D.M.Kouznetsova, J.Benavides, G.A.Pohida, K.Kuenstner, E.J.Luci, D.K.Lukacs, C.M.Davies, D.R.Dranow, D.M.Zhu, H.Sulikowski, G.Moore, W.J.Stott, G.M.Flint, A.J.Hall, M.D.Darley-Usmar, V.M.Neckers, L.M.Dang, C.V.Waterson, A.G.Simeonov, A.Jadhav, A.Maloney, D.J.

(2017) J Med Chem 60: 9184-9204

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00941
  • Primary Citation of Related Structures:  
    5W8H, 5W8I, 5W8J, 5W8K, 5W8L

  • PubMed Abstract: 

    We report the discovery and medicinal chemistry optimization of a novel series of pyrazole-based inhibitors of human lactate dehydrogenase (LDH). Utilization of a quantitative high-throughput screening paradigm facilitated hit identification, while structure-based design and multiparameter optimization enabled the development of compounds with potent enzymatic and cell-based inhibition of LDH enzymatic activity. Lead compounds such as 63 exhibit low nM inhibition of both LDHA and LDHB, submicromolar inhibition of lactate production, and inhibition of glycolysis in MiaPaCa2 pancreatic cancer and A673 sarcoma cells. Moreover, robust target engagement of LDHA by lead compounds was demonstrated using the cellular thermal shift assay (CETSA), and drug-target residence time was determined via SPR. Analysis of these data suggests that drug-target residence time (off-rate) may be an important attribute to consider for obtaining potent cell-based inhibition of this cancer metabolism target.


  • Organizational Affiliation

    National Center for Advancing Translational Sciences, National Institutes of Health , 9800 Medical Center Drive, Rockville, Maryland 20850, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
L-lactate dehydrogenase A chain
A, B, C, D
332Homo sapiensMutation(s): 0 
Gene Names: LDHAPIG19
EC: 1.1.1.27
UniProt & NIH Common Fund Data Resources
Find proteins for P00338 (Homo sapiens)
Explore P00338 
Go to UniProtKB:  P00338
PHAROS:  P00338
GTEx:  ENSG00000134333 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00338
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAI
Query on NAI

Download Ideal Coordinates CCD File 
E [auth A],
K [auth B],
N [auth C],
T [auth D]
1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE
C21 H29 N7 O14 P2
BOPGDPNILDQYTO-NNYOXOHSSA-N
9YA
Query on 9YA

Download Ideal Coordinates CCD File 
F [auth A],
L [auth B],
O [auth C],
U [auth D]
2-{3-([1,1'-biphenyl]-3-yl)-5-(cyclopropylmethyl)-4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl}-1,3-thiazole-4-carboxylic acid
C30 H26 N4 O4 S2
ALJORCZKMBZYCR-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
G [auth A]
H [auth A]
I [auth A]
J [auth A]
M [auth B]
G [auth A],
H [auth A],
I [auth A],
J [auth A],
M [auth B],
P [auth C],
Q [auth C],
R [auth C],
S [auth C],
V [auth D],
W [auth D],
X [auth D],
Y [auth D]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
9YA BindingDB:  5W8L Kd: 0.11 (nM) from 1 assay(s)
IC50: min: 24, max: 854 (nM) from 6 assay(s)
EC50: 170 (nM) from 1 assay(s)
Binding MOAD:  5W8L IC50: 32 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.176 
  • R-Value Work: 0.147 
  • Space Group: P 21 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 135.34α = 90
b = 95.34β = 90
c = 121.72γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
XSCALEdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-01-17
    Type: Initial release
  • Version 1.1: 2024-03-13
    Changes: Data collection, Database references