7N3L

Co-complex CYP46A1 with 0420 (compound 6)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.167 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Novel 3-Piperidinyl Pyridine Derivatives as Highly Potent and Selective Cholesterol 24-Hydroxylase (CH24H) Inhibitors.

Kajita, Y.Ikeda, S.Yoshikawa, M.Fukuda, H.Watanabe, E.Yano, J.Lane, W.Miyamoto, M.Ishii, T.Nishi, T.Koike, T.

(2022) J Med Chem 65: 3343-3358

  • DOI: https://doi.org/10.1021/acs.jmedchem.1c01898
  • Primary Citation of Related Structures:  
    7N3L, 7N3M

  • PubMed Abstract: 

    Cholesterol 24-hydroxylase (CH24H or CYP46A1) is a brain-specific cytochrome P450 enzyme that metabolizes cholesterol into 24 S -hydroxycholesterol (24HC) for regulating brain cholesterol homeostasis. For the development of a novel and potent CH24H inhibitor, we designed and synthesized 3,4-disubstituted pyridine derivatives using a structure-based drug design approach starting from compounds 1 (soticlestat) and 2 (thioperamide). Optimization of this series by focusing on ligand-lipophilicity efficiency value resulted in the discovery of 4-(4-methyl-1-pyrazolyl)pyridine derivative 17 (IC 50 = 8.5 nM) as a potent and highly selective CH24H inhibitor. The X-ray crystal structure of CH24H in complex with compound 17 revealed a unique binding mode. Both blood-brain barrier penetration and reduction of 24HC levels (26% reduction) in the mouse brain were confirmed by oral administration of 17 at 30 mg/kg, indicating that 17 is a promising tool for the novel and selective inhibition of CH24H.


  • Organizational Affiliation

    Research, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cholesterol 24-hydroxylase474Homo sapiensMutation(s): 0 
Gene Names: CYP46A1CYP46
EC: 1.14.14.25
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y6A2 (Homo sapiens)
Explore Q9Y6A2 
Go to UniProtKB:  Q9Y6A2
PHAROS:  Q9Y6A2
GTEx:  ENSG00000036530 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y6A2
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HEM
Query on HEM

Download Ideal Coordinates CCD File 
B [auth A]PROTOPORPHYRIN IX CONTAINING FE
C34 H32 Fe N4 O4
KABFMIBPWCXCRK-RGGAHWMASA-L
04Y (Subject of Investigation/LOI)
Query on 04Y

Download Ideal Coordinates CCD File 
D [auth A]N-cyclopropyl-1-(4-phenylpyridin-3-yl)piperidine-4-carboxamide
C20 H23 N3 O
IEDSUIIRTVCTDM-UHFFFAOYSA-N
GOL
Query on GOL

Download Ideal Coordinates CCD File 
E [auth A]GLYCEROL
C3 H8 O3
PEDCQBHIVMGVHV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A],
F [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.63 Å
  • R-Value Free: 0.200 
  • R-Value Work: 0.167 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.494α = 90
b = 63.679β = 90
c = 124.637γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data 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: 2022-02-23
    Type: Initial release
  • Version 1.1: 2022-03-16
    Changes: Database references
  • Version 1.2: 2023-10-18
    Changes: Data collection, Refinement description