7RKT

Naegleria fowleri CYP51 (NfCYP51) complex with (S)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethyl 3-(trifluoromethyl)benzoate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 

Starting Model: experimental
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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Miconazole-like Scaffold is a Promising Lead for Naegleria fowleri -Specific CYP51 Inhibitors.

Sharma, V.Madia, V.N.Tudino, V.Nguyen, J.V.Debnath, A.Messore, A.Ialongo, D.Patacchini, E.Palenca, I.Basili Franzin, S.Seguella, L.Esposito, G.Petrucci, R.Di Matteo, P.Bortolami, M.Saccoliti, F.Di Santo, R.Scipione, L.Costi, R.Podust, L.M.

(2023) J Med Chem 

  • DOI: https://doi.org/10.1021/acs.jmedchem.3c01898
  • Primary Citation of Related Structures:  
    7RKR, 7RKT, 7RKW

  • PubMed Abstract: 

    Developing drugs for brain infection by Naegleria fowleri is an unmet medical need. We used a combination of cheminformatics, target-, and phenotypic-based drug discovery methods to identify inhibitors that target an essential N. fowleri enzyme, sterol 14-demethylase (NfCYP51). A total of 124 compounds preselected in silico were tested against N. fowleri . Nine primary hits with EC 50 ≤ 10 μM were phenotypically identified. Cocrystallization with NfCYP51 focused attention on one primary hit, miconazole-like compound 2a . The S -enantiomer of 2a produced a 1.74 Å cocrystal structure. A set of analogues was then synthesized and evaluated to confirm the superiority of the S -configuration over the R -configuration and the advantage of an ether linkage over an ester linkage. The two compounds, S - 8b and S - 9b , had an improved EC 50 and K D compared to 2a . Importantly, both were readily taken up into the brain. The brain-to-plasma distribution coefficient of S - 9b was 1.02 ± 0.12, suggesting further evaluation as a lead for primary amoebic meningoencephalitis.


  • Organizational Affiliation

    Skaggs School of Pharmacy and Pharmaceutical Sciences, Center for Discovery and Innovation in Parasitic Diseases, University of California San Diego, La Jolla, California 92093, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Protein CYP51466Naegleria fowleriMutation(s): 0 
Gene Names: NF0102700
UniProt
Find proteins for A0A2H4A2U9 (Naegleria fowleri)
Explore A0A2H4A2U9 
Go to UniProtKB:  A0A2H4A2U9
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupA0A2H4A2U9
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.10 Å
  • R-Value Free: 0.239 
  • R-Value Work: 0.179 
  • R-Value Observed: 0.182 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 121.7α = 90
b = 55.19β = 100.22
c = 72.53γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XDSdata scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2022-07-27
    Type: Initial release
  • Version 1.1: 2023-10-18
    Changes: Data collection, Refinement description
  • Version 1.2: 2023-12-27
    Changes: Database references