6G1W

Crystal structure of Torpedo Californica acetylcholinesterase in complex with 2-{1-[2-(6-Chloro-1,2,3,4-tetrahydroacridin-9-ylamino)ethyl]-1H-1,2,3-triazol-4-yl}-N-[4-(hydroxy)-3-methoxybenzyl]acetamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 

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Ligand Structure Quality Assessment 


This is version 2.2 of the entry. See complete history


Literature

Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis.

Galdeano, C.Coquelle, N.Cieslikiewicz-Bouet, M.Bartolini, M.Perez, B.Clos, M.V.Silman, I.Jean, L.Colletier, J.P.Renard, P.Y.Munoz-Torrero, D.

(2018) Molecules 23

  • DOI: https://doi.org/10.3390/molecules23030634
  • Primary Citation of Related Structures:  
    6G1U, 6G1V, 6G1W

  • PubMed Abstract: 

    Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.


  • Organizational Affiliation

    Laboratory of Pharmaceutical Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain. cgaldeano@ub.edu.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Acetylcholinesterase
A, B
565Tetronarce 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
E0Z
Query on E0Z

Download Ideal Coordinates CCD File 
F [auth A],
M [auth B]
2-[1-[2-[(3-chloranylacridin-9-yl)amino]ethyl]-1,2,3-triazol-4-yl]-~{N}-[(3-methoxy-4-oxidanyl-phenyl)methyl]ethanamide
C27 H25 Cl N6 O3
UQMOCUNKULLJES-UHFFFAOYSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
J [auth B]
K [auth B]
C [auth A],
D [auth A],
E [auth A],
J [auth B],
K [auth B],
L [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
G [auth A],
H [auth A],
I [auth A],
N [auth B],
O [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.190 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.82α = 90
b = 106.81β = 90
c = 151.67γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
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: 2018-04-04
    Type: Initial release
  • Version 2.0: 2019-05-01
    Changes: Advisory, Atomic model, Data collection, Database references, Derived calculations, Polymer sequence, Source and taxonomy, Structure summary
  • Version 2.1: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary
  • Version 2.2: 2024-01-17
    Changes: Data collection, Database references, Refinement description, Structure summary