3GMD

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

PDB DOI: https://doi.org/10.2210/pdb3GMD/pdb

Classification: OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR
Organism(s): Mus musculus
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2009-03-13 Released: 2010-11-17
Deposition Author(s): Valeur, E., Lepifre, F., Roche, D., Christmann-Franck, S., Hillertz, P., Musil, D.

Experimental Data Snapshot

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

wwPDB Validation 3D Report Full Report

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

PubMed: 22901389 Search on PubMed
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.

Macromolecule Content

Total Structure Weight: 241.48 kDa
Atom Count: 17,364
Modelled Residue Count: 2,112
Deposited Residue Count: 2,112
Unique protein chains: 1

Macromolecules

Find similar proteins by:

(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Corticosteroid 11-beta-dehydrogenase isozyme 1	A, B, C, D, E A, B, C, D, E, F, G, H	264	Mus musculus	Mutation(s): 6 Gene Names: Hsd11, Hsd11b1, HSD11L EC: 1.1.1.146 (PDB Primary Data), 1.1.1.201 (UniProt)
UniProt
Find proteins for P50172 (Mus musculus) Explore P50172 Go to UniProtKB: P50172
Entity Groups
Sequence Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P50172
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NDP Query on NDP Download Ideal Coordinates CCD File SDF format, chain AA [auth G] SDF format, chain DA [auth H] SDF format, chain I [auth A] SDF format, chain K [auth B] SDF format, chain R [auth D] SDF format, chain U [auth E] SDF format, chain X [auth F] SDF format, chain N [auth C] MOL2 format, chain AA [auth G] MOL2 format, chain DA [auth H] MOL2 format, chain I [auth A] MOL2 format, chain K [auth B] MOL2 format, chain R [auth D] MOL2 format, chain U [auth E] MOL2 format, chain X [auth F] MOL2 format, chain N [auth C] mmCIF format, chain AA [auth G] mmCIF format, chain DA [auth H] mmCIF format, chain I [auth A] mmCIF format, chain K [auth B] mmCIF format, chain R [auth D] mmCIF format, chain U [auth E] mmCIF format, chain X [auth F] mmCIF format, chain N [auth C]	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		Interactions Focus chain AA [auth G] Focus chain DA [auth H] Focus chain I [auth A] Focus chain K [auth B] Focus chain N [auth C] Focus chain R [auth D] Focus chain U [auth E] Focus chain X [auth F] Interactions & Density Focus chain AA [auth G] Focus chain DA [auth H] Focus chain I [auth A] Focus chain K [auth B] Focus chain N [auth C] Focus chain R [auth D] Focus chain U [auth E] Focus chain X [auth F]
2M3 Query on 2M3 Download Ideal Coordinates CCD File SDF format, chain CA [auth G] SDF format, chain GA [auth H] SDF format, chain J [auth A] SDF format, chain M [auth B] SDF format, chain Q [auth C] SDF format, chain T [auth D] SDF format, chain W [auth E] SDF format, chain Z [auth F] MOL2 format, chain CA [auth G] MOL2 format, chain GA [auth H] MOL2 format, chain J [auth A] MOL2 format, chain M [auth B] MOL2 format, chain Q [auth C] MOL2 format, chain T [auth D] MOL2 format, chain W [auth E] MOL2 format, chain Z [auth F] mmCIF format, chain CA [auth G] mmCIF format, chain GA [auth H] mmCIF format, chain J [auth A] mmCIF format, chain M [auth B] mmCIF format, chain Q [auth C] mmCIF format, chain T [auth D] mmCIF format, chain W [auth E] mmCIF format, chain Z [auth F]	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		Interactions Focus chain CA [auth G] Focus chain GA [auth H] Focus chain J [auth A] Focus chain M [auth B] Focus chain Q [auth C] Focus chain T [auth D] Focus chain W [auth E] Focus chain Z [auth F] Interactions & Density Focus chain CA [auth G] Focus chain GA [auth H] Focus chain J [auth A] Focus chain M [auth B] Focus chain Q [auth C] Focus chain T [auth D] Focus chain W [auth E] Focus chain Z [auth F]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain BA [auth G] SDF format, chain EA [auth H] SDF format, chain FA [auth H] SDF format, chain L [auth B] SDF format, chain O [auth C] SDF format, chain P [auth C] SDF format, chain S [auth D] SDF format, chain V [auth E] SDF format, chain Y [auth F] MOL2 format, chain BA [auth G] MOL2 format, chain EA [auth H] MOL2 format, chain FA [auth H] MOL2 format, chain L [auth B] MOL2 format, chain O [auth C] MOL2 format, chain P [auth C] MOL2 format, chain S [auth D] MOL2 format, chain V [auth E] MOL2 format, chain Y [auth F] mmCIF format, chain BA [auth G] mmCIF format, chain EA [auth H] mmCIF format, chain FA [auth H] mmCIF format, chain L [auth B] mmCIF format, chain O [auth C] mmCIF format, chain P [auth C] mmCIF format, chain S [auth D] mmCIF format, chain V [auth E] mmCIF format, chain Y [auth F]	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		Interactions Focus chain BA [auth G] Focus chain EA [auth H] Focus chain FA [auth H] Focus chain L [auth B] Focus chain O [auth C] Focus chain P [auth C] Focus chain S [auth D] Focus chain V [auth E] Focus chain Y [auth F] Interactions & Density Focus chain BA [auth G] Focus chain EA [auth H] Focus chain FA [auth H] Focus chain L [auth B] Focus chain O [auth C] Focus chain P [auth C] Focus chain S [auth D] Focus chain V [auth E] Focus chain Y [auth F]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.28 ?
R-Value Free: 0.306
R-Value Work: 0.252
R-Value Observed: 0.254
Space Group: P 1 2₁ 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 127.336	α = 90
b = 70.486	β = 91.78
c = 132.956	γ = 90

Software Package:

Software Name	Purpose
AMoRE	phasing
CNX	refinement
XDS	data reduction
XDS	data scaling

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2010-11-17

Deposition Author(s):

Valeur, E.

Lepifre, F.

Roche, D.

Christmann-Franck, S.

Hillertz, P.

Musil, D.

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