4HX5

Crystal structure of 11 beta-HSD1 in complex with SAR184841

PDB DOI: https://doi.org/10.2210/pdb4HX5/pdb

Classification: OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): Yes

Deposited: 2012-11-09 Released: 2013-05-08
Deposition Author(s): Loenze, P., Schimanski-Breves, S., Engel, C.K.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.19 Å
R-Value Free: 0.199
R-Value Work: 0.163

Starting Model: experimental
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wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.2 of the entry. See complete history.

Literature

Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D

Venier, O., Pascal, C., Braun, A., Namane, C., Mougenot, P., Crespin, O., Pacquet, F., Mougenot, C., Monseau, C., Onofri, B., Dadji-Faihun, R., Leger, C., Ben-Hassine, M., Van-Pham, T., Ragot, J.L., Philippo, C., Farjot, G., Noah, L., Maniani, K., Boutarfa, A., Nicolai, E., Guillot, E., Pruniaux, M.P., Gussregen, S., Engel, C., Coutant, A.L., de Miguel, B., Castro, A.

(2013) Bioorg Med Chem Lett 23: 2414-2421

PubMed: 23478147 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2013.02.018
Primary Citation of Related Structures:
4HX5

PubMed Abstract:
Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.

Organizational Affiliation

Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. [email protected]

Macromolecule Content

Total Structure Weight: 132.62 kDa
Atom Count: 8,877
Modelled Residue Count: 1,049
Deposited Residue Count: 1,144
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	286	Homo sapiens	Mutation(s): 1 Gene Names: HSD11B1, HSD11, HSD11L EC: 1.1.1.146 (PDB Primary Data), 1.1.1.201 (UniProt)
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 Clusters	30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt Group	P28845
Sequence Annotations Expand
Reference Sequence

Small Molecules

Ligands 2 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NDP Query on NDP Download Ideal Coordinates CCD File SDF format, chain F [auth A] SDF format, chain H [auth B] SDF format, chain J [auth C] SDF format, chain L [auth D] MOL2 format, chain F [auth A] MOL2 format, chain H [auth B] MOL2 format, chain J [auth C] MOL2 format, chain L [auth D] mmCIF format, chain F [auth A] mmCIF format, chain H [auth B] mmCIF format, chain J [auth C] mmCIF format, chain L [auth D]	F [auth A], H [auth B], J [auth C], L [auth D]	NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₃₀ N₇ O₁₇ P₃ ACFIXJIJDZMPPO-NNYOXOHSSA-N		Interactions Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D] Interactions & Density Focus chain F [auth A] Focus chain H [auth B] Focus chain J [auth C] Focus chain L [auth D]
19V Query on 19V Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain G [auth B] SDF format, chain I [auth C] SDF format, chain K [auth D] MOL2 format, chain E [auth A] MOL2 format, chain G [auth B] MOL2 format, chain I [auth C] MOL2 format, chain K [auth D] mmCIF format, chain E [auth A] mmCIF format, chain G [auth B] mmCIF format, chain I [auth C] mmCIF format, chain K [auth D]	E [auth A], G [auth B], I [auth C], K [auth D]	4-[5-(4-tert-butylpiperazin-1-yl)pyridin-2-yl]-N-[(1R,2S,3S,5S,7s)-5-carbamoyltricyclo[3.3.1.1~3,7~]dec-2-yl]-3,4-dihydroquinoxaline-1(2H)-carboxamide C₃₃ H₄₅ N₇ O₂ RZUKTDWPBQOSBE-PKZLOJIYSA-N		Interactions Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D] Interactions & Density Focus chain E [auth A] Focus chain G [auth B] Focus chain I [auth C] Focus chain K [auth D]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.19 Å
R-Value Free: 0.199
R-Value Work: 0.163
Space Group: P 1 2₁ 1

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 56.399	α = 90
b = 153.491	β = 92.89
c = 73.755	γ = 90

Software Package:

Software Name	Purpose
PHASER	phasing
BUSTER	refinement
XDS	data reduction
XSCALE	data scaling

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2013-05-08

Deposition Author(s):

Loenze, P.

Schimanski-Breves, S.

Engel, C.K.

Revision History (Full details and data files)

Version 1.0: 2013-05-08
Type: Initial release
Version 1.1: 2013-06-12
Changes: Other
Version 1.2: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description