7Q1O

Crystal structure of human butyrylcholinesterase in complex with N-[(2S)-3-[(cyclohexylmethyl)amino]-2-hydroxypropyl]-3,3-diphenylpropanamide


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 2.1 of the entry. See complete history


Literature

Discovery of new, highly potent and selective inhibitors of BuChE - design, synthesis, in vitro and in vivo evaluation and crystallography studies.

Panek, D.Pasieka, A.Latacz, G.Zareba, P.Szczech, M.Godyn, J.Chantegreil, F.Nachon, F.Brazzolotto, X.Skrzypczak-Wiercioch, A.Walczak, M.Smolik, M.Salat, K.Hofner, G.Wanner, K.Wieckowska, A.Malawska, B.

(2023) Eur J Med Chem 249: 115135-115135

  • DOI: https://doi.org/10.1016/j.ejmech.2023.115135
  • Primary Citation of Related Structures:  
    7Q1M, 7Q1N, 7Q1O, 7Q1P

  • PubMed Abstract: 

    The symptomatic and disease-modifying effects of butyrylcholinesterase (BuChE) inhibitors provide an encouraging premise for researching effective treatments for Alzheimer's disease. Here, we examined a series of compounds with a new chemical scaffold based on 3-(cyclohexylmethyl)amino-2-hydroxypropyl, and we identified a highly selective hBuChE inhibitor (29). Based on extensive in vitro and in vivo evaluations of the compound and its enantiomers, (R)-29 was identified as a promising candidate for further development. Compound (R)-29 is a potent hBuChE inhibitor (IC 50  = 40 nM) with selectivity over AChE and relevant off-targets, including H 1 , M 1 , α 1A and β 1 receptors. The compound displays high metabolic stability on human liver microsomes (90% of the parent compound after 2 h of incubation), and its safety was confirmed through examining the cytotoxicity on the HepG2 cell line (LC 50  = 2.85 μM) and hERG inhibition (less than 50% at 10 μM). While (rac)-29 lacked an effect in vivo and showed limited penetration to the CNS in pharmacokinetics studies, compound (R)-29 exhibited a procognitive effect at 15 mg/kg in the passive avoidance task in scopolamine-treated mice.


  • Organizational Affiliation

    Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna St. 9, 30-688, Kraków, Poland. Electronic address: [email protected].


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

Help

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, D
3N-Glycosylation
Glycosylation Resources
GlyTouCan:  G21290RB
GlyCosmos:  G21290RB
GlyGen:  G21290RB
Small Molecules
Ligands 7 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9CI (Subject of Investigation/LOI)
Query on 9CI

Download Ideal Coordinates CCD File 
I [auth A]N-[(2S)-3-(cyclohexylmethylamino)-2-oxidanyl-propyl]-3,3-diphenyl-propanamide
C25 H34 N2 O2
AGQFRFDHZZBREO-QHCPKHFHSA-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
SO4
Query on SO4

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

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

Download Ideal Coordinates CCD File 
L [auth A]GLYCOLIC ACID
C2 H4 O3
AEMRFAOFKBGASW-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
T [auth A]CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
NA
Query on NA

Download Ideal Coordinates CCD File 
S [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.65 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.170 
  • R-Value Observed: 0.172 
  • Space Group: I 4 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 154.81α = 90
b = 154.81β = 90
c = 135.25γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
Cootmodel building
XDSdata reduction
XSCALEdata scaling
PHASERphasing

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-4210

Revision History  (Full details and data files)

  • Version 1.0: 2022-11-16
    Type: Initial release
  • Version 1.1: 2023-02-01
    Changes: Database references
  • Version 1.2: 2023-02-08
    Changes: Database references
  • Version 2.0: 2023-11-15
    Changes: Atomic model, Data collection
  • Version 2.1: 2024-02-07
    Changes: Refinement description