3GMD

Structure-based design of 7-Azaindole-pyrrolidines as inhibitors of 11beta-Hydroxysteroid-Dehydrogenase type I


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.306 
  • R-Value Work: 0.252 
  • R-Value Observed: 0.254 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Structure-based design of 7-azaindole-pyrrolidine amides as inhibitors of 11 beta-hydroxysteroid dehydrogenase type I.

Valeur, E.Christmann-Franck, S.Lepifre, F.Carniato, D.Cravo, D.Charon, C.Bozec, S.Musil, D.Hillertz, P.Doare, L.Schmidlin, F.Lecomte, M.Schultz, M.Roche, D.

(2012) Bioorg Med Chem Lett 22: 5909-5914

  • DOI: https://doi.org/10.1016/j.bmcl.2012.07.070
  • Primary Citation of Related Structures:  
    3GMD

  • PubMed Abstract: 

    Indole-pyrrolidines were identified as inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) by high-throughput screening. Optimisation of the initial hit through structure-based design led to 7-azaindole-derivatives, with the best analogues displaying single digit nanomolar IC(50) potency. The modeling hypotheses were confirmed by solving the X-ray co-crystal structure of one of the lead compounds. These compounds were selective against 11β-hydroxysteroid dehydrogenase type 2 (selectivity ratio >200) and exhibited good inhibition of 11β-HSD1 (IC(50)<1μM) in a cellular model (3T3L1 adipocytes).


  • Organizational Affiliation

    Merck-Serono S.A., 9, Chemin des Mines, 1202 Geneva, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Corticosteroid 11-beta-dehydrogenase isozyme 1
A, B, C, D, E
A, B, C, D, E, F, G, H
264Mus musculusMutation(s): 6 
Gene Names: Hsd11Hsd11b1HSD11L
EC: 1.1.1.146
UniProt
Find proteins for P50172 (Mus musculus)
Explore P50172 
Go to UniProtKB:  P50172
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP50172
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP

Download Ideal Coordinates CCD File 
AA [auth G]
DA [auth H]
I [auth A]
K [auth B]
N [auth C]
AA [auth G],
DA [auth H],
I [auth A],
K [auth B],
N [auth C],
R [auth D],
U [auth E],
X [auth F]
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
2M3
Query on 2M3

Download Ideal Coordinates CCD File 
CA [auth G]
GA [auth H]
J [auth A]
M [auth B]
Q [auth C]
CA [auth G],
GA [auth H],
J [auth A],
M [auth B],
Q [auth C],
T [auth D],
W [auth E],
Z [auth F]
2-methyl-3-{(3S)-1-[(1-pyridin-2-ylcyclopropyl)carbonyl]pyrrolidin-3-yl}-1H-pyrrolo[2,3-b]pyridine
C21 H22 N4 O
HUWRMRPEILCPLL-OAHLLOKOSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
BA [auth G]
EA [auth H]
FA [auth H]
L [auth B]
O [auth C]
BA [auth G],
EA [auth H],
FA [auth H],
L [auth B],
O [auth C],
P [auth C],
S [auth D],
V [auth E],
Y [auth F]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.306 
  • R-Value Work: 0.252 
  • R-Value Observed: 0.254 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 127.336α = 90
b = 70.486β = 91.78
c = 132.956γ = 90
Software Package:
Software NamePurpose
AMoREphasing
CNXrefinement
XDSdata reduction
XDSdata scaling

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2010-11-17
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2013-09-04
    Changes: Database references
  • Version 1.3: 2017-11-01
    Changes: Advisory, Refinement description
  • Version 1.4: 2024-02-21
    Changes: Advisory, Data collection, Database references, Derived calculations