5IXY

Lactate Dehydrogenase in complex with hydroxylactam inhibitor compound 31: (2~{S})-5-(2-chlorophenyl)sulfanyl-2-(4-morpholin-4-ylphenyl)-4-oxidanyl-2-thiophen-3-yl-1,3-dihydropyridin-6-one


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.237 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Cell Active Hydroxylactam Inhibitors of Human Lactate Dehydrogenase with Oral Bioavailability in Mice.

Purkey, H.E.Robarge, K.Chen, J.Chen, Z.Corson, L.B.Ding, C.Z.DiPasquale, A.G.Dragovich, P.S.Eigenbrot, C.Evangelista, M.Fauber, B.P.Gao, Z.Ge, H.Hitz, A.Ho, Q.Labadie, S.S.Lai, K.W.Liu, W.Liu, Y.Li, C.Ma, S.Malek, S.O'Brien, T.Pang, J.Peterson, D.Salphati, L.Sideris, S.Ultsch, M.Wei, B.Yen, I.Yue, Q.Zhang, H.Zhou, A.

(2016) ACS Med Chem Lett 7: 896-901

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00190
  • Primary Citation of Related Structures:  
    5IXS, 5IXY

  • PubMed Abstract: 

    A series of trisubstituted hydroxylactams was identified as potent enzymatic and cellular inhibitors of human lactate dehydrogenase A. Utilizing structure-based design and physical property optimization, multiple inhibitors were discovered with <10 μM lactate IC 50 in a MiaPaca2 cell line. Optimization of the series led to 29 , a potent cell active molecule (MiaPaca2 IC 50 = 0.67 μM) that also possessed good exposure when dosed orally to mice.


  • Organizational Affiliation

    Genentech, Inc. , 1 DNA Way, South San Francisco, California 94080, 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
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 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAD
Query on NAD

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B],
N [auth C],
R [auth D]
NICOTINAMIDE-ADENINE-DINUCLEOTIDE
C21 H27 N7 O14 P2
BAWFJGJZGIEFAR-NNYOXOHSSA-N
GN2
Query on GN2

Download Ideal Coordinates CCD File 
H [auth A],
M [auth B],
Q [auth C],
S [auth D]
(2~{S})-5-(2-chlorophenyl)sulfanyl-2-(4-morpholin-4-ylphenyl)-4-oxidanyl-2-thiophen-3-yl-1,3-dihydropyridin-6-one
C25 H23 Cl N2 O3 S2
SUFXXEIVBZJOAP-VWLOTQADSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
J [auth B]
K [auth B]
L [auth B]
F [auth A],
G [auth A],
J [auth B],
K [auth B],
L [auth B],
O [auth C],
P [auth C]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.279 
  • R-Value Work: 0.236 
  • R-Value Observed: 0.237 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.452α = 90
b = 80.696β = 97.9
c = 102.236γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
SCALEPACKdata 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: 2016-09-14
    Type: Initial release
  • Version 1.1: 2016-11-09
    Changes: Database references
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description