9GIB

NMDA bound to compound 380


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.203 

Starting Model: experimental
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Literature

Advancements in NMDA Receptor-Targeted Antidepressants: From d-Cycloserine Discovery to Preclinical Efficacy of Lu AF90103.

Ascic, E.Marigo, M.David, L.Frisch Herrik, K.Grupe, M.Hougaard, C.Mork, A.Jones, C.R.Badolo, L.Frederiksen, K.Boonen, H.C.M.Jensen, H.S.Kilburn, J.P.

(2024) J Med Chem 

  • DOI: https://doi.org/10.1021/acs.jmedchem.4c01477
  • Primary Citation of Related Structures:  
    9GIB, 9GIC, 9GID, 9GIE, 9GIF, 9GIG, 9GJ1

  • PubMed Abstract: 

    The discovery of d-cycloserine ( DCS ), a partial agonist of the NMDA receptor that exhibits antidepressant effects without the psychotomimetic effects of ketamine, has fueled interest in new NMDA-targeting antidepressants. Our objective was to identify potent partial agonists mirroring DCS , particularly tailored for the GluN2B subtype of the NMDA receptor. Through a structure-based drug design approach, we discovered compound 42d . This compound acts as a partial agonist of the GluN1/GluN2B complex, exhibiting 24% efficacy, and has an EC 50 value of 78 nM. Subsequent investigations led us to 42e (Lu AF90103), a methyl ester prodrug of 42d capable of penetrating the blood-brain barrier, as confirmed by rat microdialysis studies. In different rat in vivo models relevant to neuropsychiatric diseases, administering 42e led to 42d demonstrating both acute effects, observed in a seizure model and EEG, and lasting effects in the stress-sensitive hippocampal pathway and an antidepressant-sensitive model.


  • Organizational Affiliation

    Neuroscience Drug Discovery Denmark, H. Lundbeck A/S, 9 Ottiliavej, Valby, DK-2500 Copenhagen, Denmark.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Glutamate receptor285Rattus norvegicusMutation(s): 0 
Gene Names: Grin2a
UniProt
Find proteins for G3V9C5 (Rattus norvegicus)
Explore G3V9C5 
Go to UniProtKB:  G3V9C5
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupG3V9C5
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Isoform 1 of Glutamate receptor ionotropic, NMDA 1291Homo sapiensMutation(s): 0 
Gene Names: GRIN1NMDAR1
UniProt & NIH Common Fund Data Resources
Find proteins for Q05586 (Homo sapiens)
Explore Q05586 
Go to UniProtKB:  Q05586
PHAROS:  Q05586
GTEx:  ENSG00000176884 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ05586
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.256 
  • R-Value Work: 0.203 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 53.972α = 90
b = 90.036β = 90
c = 123.174γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
Aimlessdata scaling
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

  • Version 1.0: 2024-11-27
    Type: Initial release