6I0B

Human butyrylcholinesterase in complex with the S enantiomer of a chlorotacrine-tryptophan multi-target inhibitor.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.192 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Novel tacrine-tryptophan hybrids: Multi-target directed ligands as potential treatment for Alzheimer's disease.

Chalupova, K.Korabecny, J.Bartolini, M.Monti, B.Lamba, D.Caliandro, R.Pesaresi, A.Brazzolotto, X.Gastellier, A.J.Nachon, F.Pejchal, J.Jarosova, M.Hepnarova, V.Jun, D.Hrabinova, M.Dolezal, R.Zdarova Karasova, J.Mzik, M.Kristofikova, Z.Misik, J.Muckova, L.Jost, P.Soukup, O.Benkova, M.Setnicka, V.Habartova, L.Chvojkova, M.Kleteckova, L.Vales, K.Mezeiova, E.Uliassi, E.Valis, M.Nepovimova, E.Bolognesi, M.L.Kuca, K.

(2019) Eur J Med Chem 168: 491-514

  • DOI: https://doi.org/10.1016/j.ejmech.2019.02.021
  • Primary Citation of Related Structures:  
    5NUU, 6I0B, 6I0C

  • PubMed Abstract: 

    A combination of tacrine and tryptophan led to the development of a new family of heterodimers as multi-target agents with potential to treat Alzheimer's disease. Based on the in vitro biological profile, compound S-K1035 was found to be the most potent inhibitor of human acetylcholinesterase (hAChE) and human butyrylcholinesterase (hBChE), demonstrating balanced IC 50 values of 6.3 and 9.1 nM, respectively. For all the tacrine-tryptophan heterodimers, favorable inhibitory effect on hAChE as well as on hBChE was coined to the optimal spacer length ranging from five to eight carbon atoms between these two pharmacophores. S-K1035 also showed good ability to inhibit Aβ 42 self-aggregation (58.6 ± 5.1% at 50 μM) as well as hAChE-induced Aβ 40 aggregation (48.3 ± 6.3% at 100 μM). The X-ray crystallographic analysis of TcAChE in complex with S-K1035 pinpointed the utility of the hybridization strategy applied and the structures determined with the two K1035 enantiomers in complex with hBChE could explain the higher inhibition potency of S-K1035. Other in vitro evaluations predicted the ability of S-K1035 to cross blood-brain barrier and to exert a moderate inhibition potency against neuronal nitric oxide synthase. Based on the initial promising biochemical data and a safer in vivo toxicity compared to tacrine, S-K1035 was administered to scopolamine-treated rats being able to dose-dependently revert amnesia.


  • Organizational Affiliation

    National Institute of Mental Health, Topolova 748, 250 67, Klecany, Czech Republic; Department of Chemistry, University of Hradec Kralove, Rokitanskeho 62, 500 03, Hradec Kralove, Czech Republic.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cholinesterase529Homo sapiensMutation(s): 4 
Gene Names: BCHECHE1
EC: 3.1.1.8
UniProt & NIH Common Fund Data Resources
Find proteins for P06276 (Homo sapiens)
Explore P06276 
Go to UniProtKB:  P06276
PHAROS:  P06276
GTEx:  ENSG00000114200 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP06276
Sequence Annotations
Expand
  • Reference Sequence
Oligosaccharides

Help

Entity ID: 2
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose
B
2N-Glycosylation
Glycosylation Resources
GlyTouCan:  G86851RC
GlyCosmos:  G86851RC
GlyGen:  G86851RC
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
C, D
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G21290RB
GlyCosmos:  G21290RB
GlyGen:  G21290RB
Small Molecules
Ligands 6 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9A5 (Subject of Investigation/LOI)
Query on 9A5

Download Ideal Coordinates CCD File 
I [auth A](2~{S})-2-azanyl-~{N}-[6-[(6-chloranyl-1,2,3,4-tetrahydroacridin-9-yl)amino]hexyl]-3-(1~{H}-indol-3-yl)propanamide
C30 H36 Cl N5 O
MSZVAOQNSCIOAB-VWLOTQADSA-N
NAG
Query on NAG

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

Download Ideal Coordinates CCD File 
H [auth A]2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
M [auth A],
N [auth A],
O [auth A],
P [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
GOL
Query on GOL

Download Ideal Coordinates CCD File 
J [auth A],
K [auth A],
L [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
Q [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Binding Affinity Annotations 
IDSourceBinding Affinity
9A5 Binding MOAD:  6I0B IC50: 9.1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.38 Å
  • R-Value Free: 0.244 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.192 
  • Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 154.351α = 90
b = 154.351β = 90
c = 128.039γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
autoPROCdata collection
Aimlessdata scaling
PHASERphasing
Cootmodel building

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
French Ministry of Armed ForcesFrancePDH-2-NRBC-3-3201

Revision History  (Full details and data files)

  • Version 1.0: 2019-03-27
    Type: Initial release
  • Version 1.1: 2019-08-14
    Changes: Data collection, Database references
  • Version 1.2: 2019-08-21
    Changes: Data collection, Database references
  • Version 1.3: 2020-07-08
    Changes: Data collection
  • Version 2.0: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Atomic model, Data collection, Derived calculations, Refinement description, Structure summary
  • Version 2.1: 2024-01-24
    Changes: Data collection, Database references, Refinement description, Structure summary