4QO7

Lactate Dehydrogenase A in complex with substituted 3-Hydroxy-2-mercaptocyclohex-2-enone compound 7


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.14 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 

Starting Model: experimental
View more details

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.

Dragovich, P.S.Fauber, B.P.Boggs, J.Chen, J.Corson, L.B.Ding, C.Z.Eigenbrot, C.Ge, H.Giannetti, A.M.Hunsaker, T.Labadie, S.Li, C.Liu, Y.Liu, Y.Ma, S.Malek, S.Peterson, D.Pitts, K.E.Purkey, H.E.Robarge, K.Salphati, L.Sideris, S.Ultsch, M.VanderPorten, E.Wang, J.Wei, B.Xu, Q.Yen, I.Yue, Q.Zhang, H.Zhang, X.Zhou, A.

(2014) Bioorg Med Chem Lett 24: 3764-3771

  • DOI: https://doi.org/10.1016/j.bmcl.2014.06.076
  • Primary Citation of Related Structures:  
    4QO7, 4QO8

  • PubMed Abstract: 

    A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7 μM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18 μM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%).


  • Organizational Affiliation

    Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA. Electronic address: [email protected].


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
331Homo 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 5 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAI
Query on NAI

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B],
K [auth C],
N [auth D]
1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE
C21 H29 N7 O14 P2
BOPGDPNILDQYTO-NNYOXOHSSA-N
36V
Query on 36V

Download Ideal Coordinates CCD File 
G [auth A],
M [auth C],
O [auth D]
trans-2-[(2-nitrophenyl)sulfanyl]-5-phenylcyclohexane-1,3-dione
C18 H15 N O4 S
CVKXTYKGXUQQPQ-KTXOBNNYSA-N
EPE
Query on EPE

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B],
L [auth C]
4-(2-HYDROXYETHYL)-1-PIPERAZINE ETHANESULFONIC ACID
C8 H18 N2 O4 S
JKMHFZQWWAIEOD-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
P [auth D]SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
2OP
Query on 2OP

Download Ideal Coordinates CCD File 
I [auth B](2S)-2-HYDROXYPROPANOIC ACID
C3 H6 O3
JVTAAEKCZFNVCJ-REOHCLBHSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.14 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.160 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 168.481α = 90
b = 81.101β = 117.38
c = 120.307γ = 90
Software Package:
Software NamePurpose
Blu-Icedata collection
PHASERphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-07-16
    Type: Initial release
  • Version 1.1: 2014-08-13
    Changes: Database references
  • Version 1.2: 2014-09-03
    Changes: Database references
  • Version 1.3: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description
  • Version 1.4: 2023-12-06
    Changes: Data collection