9NNI | pdb_00009nni

Crystal structure of CYP46A1 with cyclopropyl[(4M)-4-(1,3-oxazol-5-yl)-6-(trifluoromethyl)-1H-indol-1-yl]methanone (compound 2b)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free: 
    0.222 (Depositor), 0.222 (DCC) 
  • R-Value Work: 
    0.197 (Depositor), 0.197 (DCC) 
  • R-Value Observed: 
    0.198 (Depositor) 

Starting Model: experimental
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Literature

Structure-based design of a novel series of cholesterol 24-hydroxylase (CH24H) inhibitors bearing 1,3-oxazole as a heme-iron binding group.

Ito, Y.Hasui, T.Kimura, E.Nomura, I.Fukuda, H.Ando, H.K.Watanabe, E.Yano, J.Skene, R.Miyamoto, M.Ishii, T.Nishi, T.Koike, T.

(2025) Bioorg Med Chem 128: 118280-118280

  • DOI: https://doi.org/10.1016/j.bmc.2025.118280
  • Primary Citation of Related Structures:  
    9NNA, 9NNE, 9NNI

  • PubMed Abstract: 

    Herein, we describe the design, synthesis, and pharmacological evaluation of novel 1,3-oxazole-based inhibitors of cholesterol 24-hydroxylase (CH24H; CYP46A1), a brain-specific cytochrome P450 (CYP) enzyme that metabolizes cholesterol to 24Shydroxycholesterol (24HC). Starting with compound 1a, a scaffold-hopping approach using structure-based drug design identified a series of imidazo[1,2-a]pyridine-3- carboxamide derivatives as novel CH24H inhibitors. Subsequent optimization guided by ligand-lipophilicity efficiency metrics resulted in the discovery of 3k (IC 50  = 4.5 nM) with potent and selective CH24H inhibition. Oral administration of compound 3k at 10 mg/kg resulted in brain penetration and 24HC reduction in the mouse brain. These results suggest that 1,3-oxazole is a promising heme-iron binder which can provide potent and selective inhibitors against CYP enzymes, including CH24H.


  • Organizational Affiliation

    Research, Takeda Pharmaceutical Company Ltd, 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
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.70 Å
  • R-Value Free:  0.222 (Depositor), 0.222 (DCC) 
  • R-Value Work:  0.197 (Depositor), 0.197 (DCC) 
  • R-Value Observed: 0.198 (Depositor) 
Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.463α = 90
b = 63.777β = 90
c = 124.214γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data scaling
HKL-2000data reduction
PHASERphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Not funded--

Revision History  (Full details and data files)

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