9I03 | pdb_00009i03

Structure of recombinant human butyrylcholinesterase in complex with (R)-N-((1-benzylpyrrolidin-3-yl)methyl)-N-methylnaphthalene-2-sulfonamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.56 Å
  • R-Value Free: 
    0.238 (Depositor), 0.235 (DCC) 
  • R-Value Work: 
    0.185 (Depositor), 0.186 (DCC) 
  • R-Value Observed: 
    0.188 (Depositor) 

Starting Model: experimental
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Literature

Lead Optimization of a Butyrylcholinesterase Inhibitor for the Treatment of Alzheimer's Disease.

Kosak, U.Strasek Benedik, N.Knez, D.Zakelj, S.Trontelj, J.Pislar, A.Horvat, S.Bolje, A.Znidarsic, N.Grgurevic, N.Svara, T.Kljun, J.Skrzypczak-Wiercioch, A.Lv, B.Xiong, Y.Wang, Q.Bian, R.Shao, J.Dias, J.Nachon, F.Brazzolotto, X.Stojan, J.Sun, H.Salat, K.Gobec, S.

(2025) J Med Chem 68: 11693-11723

  • DOI: https://doi.org/10.1021/acs.jmedchem.5c00577
  • Primary Citation of Related Structures:  
    9I02, 9I03

  • PubMed Abstract: 

    Butyrylcholinesterase (BChE) is a promising drug target for alleviating the symptoms of canine cognitive dysfunction (CCD) and Alzheimer's disease (AD). We have recently developed lead compound 2 , a racemic, nanomolar BChE inhibitor with procognitive effects in mice with scopolamine-induced AD-like symptoms and dogs suffering from CCD. To overcome its modest brain exposure, we developed compound ( R )-(-)-3 , a more potent BChE inhibitor with a 7-fold higher in vivo brain exposure. It has procognitive effects in mice with scopolamine-induced AD-like symptoms and, superior to compound 2 , also in mice with Aβ 1-42 -induced AD-like symptoms. Compound ( R )-(-)-3 produces no cholinergic adverse effects or motor deficits and has no acute toxic effects in mice. This makes sulfonamide ( R )-(-)-3 an optimized lead compound for alleviating the symptoms of AD.


  • Organizational Affiliation

    Faculty of Pharmacy, University of Ljubljana, Aškerčeva cesta 7, 1000 Ljubljana, Slovenia.


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
Glycosylation
Glycosylation Sites: 6Go to GlyGen: P06276-1
Sequence Annotations
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  • Reference Sequence
Oligosaccharides

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Entity ID: 2
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
B, C
3N-Glycosylation
Entity ID: 3
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose
D
2N-Glycosylation
Entity ID: 4
MoleculeChains Length2D Diagram Glycosylation3D Interactions
alpha-D-mannopyranose-(1-3)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose
E
5N-Glycosylation
Small Molecules
Ligands 8 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
A1IYQ (Subject of Investigation/LOI)
Query on A1IYQ

Download Ideal Coordinates CCD File 
M [auth A]~{N}-methyl-~{N}-[[(3~{R})-1-(phenylmethyl)pyrrolidin-3-yl]methyl]naphthalene-2-sulfonamide
C23 H26 N2 O2 S
FNPKLEUPADIGIY-UHFFFAOYSA-N
SIA
Query on SIA

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L [auth A]N-acetyl-alpha-neuraminic acid
C11 H19 N O9
SQVRNKJHWKZAKO-YRMXFSIDSA-N
NAG
Query on NAG

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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 
I [auth A]2-(N-MORPHOLINO)-ETHANESULFONIC ACID
C6 H13 N O4 S
SXGZJKUKBWWHRA-UHFFFAOYSA-N
SO4
Query on SO4

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

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H [auth A],
J [auth A],
K [auth A]
GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
PPI
Query on PPI

Download Ideal Coordinates CCD File 
N [auth A]PROPANOIC ACID
C3 H6 O2
XBDQKXXYIPTUBI-UHFFFAOYSA-N
CL
Query on CL

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S [auth A],
T [auth A]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.56 Å
  • R-Value Free:  0.238 (Depositor), 0.235 (DCC) 
  • R-Value Work:  0.185 (Depositor), 0.186 (DCC) 
  • R-Value Observed: 0.188 (Depositor) 
Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 153.6α = 90
b = 153.6β = 90
c = 127.11γ = 90
Software Package:
Software NamePurpose
MxCuBEdata collection
XDSdata reduction
XSCALEdata scaling
PHASERphasing
Cootmodel building
PHENIXrefinement

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
French Ministry of Armed ForcesFranceNBC-5-C-2316

Revision History  (Full details and data files)

  • Version 1.0: 2025-07-02
    Type: Initial release