6EZG

Torpedo californica AChE in complex with indolic multi-target directed ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Novel multitarget-directed ligands targeting acetylcholinesterase and sigma1receptors as lead compounds for treatment of Alzheimer's disease: Synthesis, evaluation, and structural characterization of their complexes with acetylcholinesterase.

Lalut, J.Santoni, G.Karila, D.Lecoutey, C.Davis, A.Nachon, F.Silman, I.Sussman, J.Weik, M.Maurice, T.Dallemagne, P.Rochais, C.

(2018) Eur J Med Chem 162: 234-248

  • DOI: https://doi.org/10.1016/j.ejmech.2018.10.064
  • Primary Citation of Related Structures:  
    6EZG, 6EZH

  • PubMed Abstract: 

    Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT 4 receptor, which displays promising activities in vivo. Pharmacomodulation of donecopride allowed us to develop a novel series of indole derivatives possessing interesting in vitro activities toward AChE and the σ 1 receptor. The crystal structures of complexes of the most promising compounds with Torpedo californica AChE were solved in order to further understand their mode of inhibition.


  • Organizational Affiliation

    Centre d'Etudes et de Recherche sur le Médicament de Normandie, Normandie Univ, UNICAEN, CERMN, 14000, Caen, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetylcholinesterase
A, B
537Tetronarce californicaMutation(s): 0 
EC: 3.1.1.7
UniProt
Find proteins for P04058 (Tetronarce californica)
Explore P04058 
Go to UniProtKB:  P04058
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04058
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
C6K (Subject of Investigation/LOI)
Query on C6K

Download Ideal Coordinates CCD File 
E [auth A],
H [auth B]
1-(7-chloranyl-4-methoxy-1~{H}-indol-5-yl)-3-[1-(phenylmethyl)piperidin-4-yl]propan-1-one
C24 H27 Cl N2 O2
BXNNACCQTQBSOO-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A],
F [auth B],
G [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
I [auth B],
J [auth B]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.20 Å
  • R-Value Free: 0.237 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.711α = 90
b = 106.996β = 90
c = 150.494γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
Aimlessdata 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: 2018-11-21
    Type: Initial release
  • Version 1.1: 2018-11-28
    Changes: Data collection, Database references, Structure summary
  • Version 1.2: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary