3PDJ

Crystal Structure of Human 11-beta-Hydroxysteroid Dehydrogenase 1 (11b-HSD1) in Complex with 4,4-Disubstituted Cyclohexylbenzamide Inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.212 

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Literature

Synthesis and Optimization of Novel 4,4-Disubstituted Cyclohexylbenzamide Derivatives as Potent 11beta-HSD1 Inhibitors

Sun, D., Wang, Z., Caille, S., DeGraffenreid, M., Gonzalez-Lopez de Turiso, F., Hungate, R., Jaen, J.C., Jiang, B., Julian, L.D., Kelly, R., McMinn, D.L., Kaizerman, J., Rew, Y., Sudom, A., Tu, H., Ursu, S., Walker, N., Willcockson, M., Yan, X., Ye, Q., Powers, J.P.

(2011) Bioorg Med Chem Lett 21: 405-410

  • DOI: https://doi.org/10.1016/j.bmcl.2010.10.129
  • Primary Citation of Related Structures:  
    3PDJ

  • PubMed Abstract: 

    The synthesis and SAR of a series of 4,4-disubstituted cyclohexylbenzamide inhibitors of 11β-HSD1 are described. Optimization rapidly led to potent, highly selective, and orally bioavailable inhibitors demonstrating efficacy in both rat and non-human primate ex vivo pharmacodynamic models.

    • Organizational Affiliation: 

    Amgen Inc, 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. daqings@amgen.com


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Corticosteroid 11-beta-dehydrogenase isozyme 1
A, B
273Homo sapiensMutation(s): 1 
Gene Names: HSD11, HSD11B1, HSD11L
EC: 1.1.1.146
UniProt & NIH Common Fund Data Resources
Find proteins for P28845 (Homo sapiens)
Explore P28845 
Go to UniProtKB:  P28845
PHAROS:  P28845
GTEx:  ENSG00000117594 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28845
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NAP
Query on NAP
Download Ideal Coordinates CCD File 
D [auth A],
F [auth B]		NADP NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H28 N7 O17 P3
XJLXINKUBYWONI-NNYOXOHSSA-N
3PJ
Query on 3PJ
Download Ideal Coordinates CCD File 
C [auth A],
E [auth B]		N-[trans-4-(3-amino-3-oxopropyl)-4-phenylcyclohexyl]-N-cyclopropyl-4-[(1S)-2,2,2-trifluoro-1-hydroxy-1-methylethyl]benzamide
C28 H33 F3 N2 O3
GGXWRFSOCBTDDI-YGPDHOBYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
3PJ BindingDB:  3PDJ IC50: min: 0.8, max: 37 (nM) from 4 assay(s)
Binding MOAD:  3PDJ IC50: 14 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.241 
  • R-Value Work: 0.211 
  • R-Value Observed: 0.212 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 107.044α = 90
b = 107.044β = 90
c = 132.918γ = 120
Software Package:
Software NamePurpose
SCALAdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
MOSFLMdata reduction

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-05
    Type: Initial release
  • Version 1.1: 2024-02-21
    Changes: Data collection, Database references, Derived calculations