3VHU

Mineralocorticoid receptor ligand-binding domain with spironolactone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Identification of Benzoxazin-3-one Derivatives as Novel, Potent, and Selective Nonsteroidal Mineralocorticoid Receptor Antagonists

Hasui, T.Matsunaga, N.Ora, T.Ohyabu, N.Nishigaki, N.Imura, Y.Igata, Y.Matsui, H.Motoyaji, T.Tanaka, T.Habuka, N.Sogabe, S.Ono, M.Siedem, C.S.Tang, T.P.Gauthier, C.De Meese, L.A.Boyd, S.A.Fukumoto, S.

(2011) J Med Chem 54: 8616-8631

  • DOI: https://doi.org/10.1021/jm2011645
  • Primary Citation of Related Structures:  
    3VHU, 3VHV

  • PubMed Abstract: 

    Mineralocorticoid receptor (MR) blockade has come into focus as a promising approach for the treatment of cardiovascular diseases such as hypertension and congestive heart failure. In order to identify a novel class of nonsteroidal MR antagonists that exhibit significant potency and good selectivity over other steroidal hormone receptors, we designed a novel series of benzoxazin-3-one derivatives and synthesized them from 6-(7H-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazin-6-yl)-2H-1,4-benzoxazin-3(4H)-one (1a), high-throughput screening (HTS) hit compound. Our design was based on a crystal structure of an MR/compound complex and a docking model. In the course of lead generation from 1a, a 1,2-diaryl framework was characterized as a key structure with high binding affinity. On the basis of scaffold hopping and optimization studies, benzoxazin-3-one derivatives possessing 1-phenyl-3-trifluoromethylpyrazol-5-yl moiety at the 6-position were identified as a novel series of potent and selective MR antagonists. Among these compounds, 6-[1-(4-fluoro-2-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]-2H-1,4-benzoxazin-3(4H)-one (14n) showed highly potent activity and good selectivity and also exhibited a significant antihypertensive effect in deoxycorticosterone acetate-salt hypertensive rats. On the basis of these results, compound 14n was progressed for further pharmacological evaluation.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd., 26-1, Muraoka-higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. Tomoaki_Hasui@takeda.co.jp


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mineralocorticoid receptor294Homo sapiensMutation(s): 2 
Gene Names: NR3C2MCRMLR
UniProt & NIH Common Fund Data Resources
Find proteins for P08235 (Homo sapiens)
Explore P08235 
Go to UniProtKB:  P08235
PHAROS:  P08235
GTEx:  ENSG00000151623 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08235
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
SNL
Query on SNL

Download Ideal Coordinates CCD File 
B [auth A]SPIRONOLACTONE
C24 H32 O4 S
LXMSZDCAJNLERA-ZHYRCANASA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
SNL BindingDB:  3VHU Ki: min: 2.32, max: 5 (nM) from 2 assay(s)
IC50: min: 1.6, max: 60 (nM) from 6 assay(s)
PDBBind:  3VHU IC50: 49 (nM) from 1 assay(s)
Binding MOAD:  3VHU IC50: 49 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.246 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.526α = 90
b = 171.509β = 90
c = 42.358γ = 90
Software Package:
Software NamePurpose
MOLREPphasing
REFMACrefinement
HKL-2000data reduction
SCALEPACKdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-12-28
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary