4K26

4,4-Dioxo-5,6-dihydro-[1,4,3]oxathiazines, a novel class of 11 -HSD1 inhibitors for the treatment of diabetes

PDB DOI: https://doi.org/10.2210/pdb4K26/pdb

Classification: OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR
Organism(s): Mus musculus
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2013-04-08 Released: 2014-04-09
Deposition Author(s): Loenze, P., Schimanski-Breves, S., Vonderheyden, C., Engel, C.K.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.21 Å
R-Value Free: 0.208
R-Value Work: 0.166
R-Value Observed: 0.168

Starting Model: experimental
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Ligand Structure Quality Assessment

This is version 1.1 of the entry. See complete history.

Literature

1,1-Dioxo-5,6-dihydro-[4,1,2]oxathiazines, a novel class of 11-HSD1 inhibitors for the treatment of diabetes.

Bohme, T., Engel, C.K., Farjot, G., Gussregen, S., Haack, T., Tschank, G., Ritter, K.

(2013) Bioorg Med Chem Lett 23: 4685-4691

PubMed: 23845218 Search on PubMed
DOI: https://doi.org/10.1016/j.bmcl.2013.05.102
Primary Citation of Related Structures:
4K1L, 4K26

PubMed Abstract:
Racemic cis-1,1-dioxo-5,6-dihydro-[4,1,2]oxathiazine derivative 4a was isolated as an impurity in a sample of a hit from a HTS campaign on 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). After separation by chiral chromatography the 4a-S, 8a-R enantiomer of compound 4a was identified as the true, potent enzyme inhibitor. The cocrystal structure of 4a with human and murine 11ß-HSD1 revealed the unique binding mode of the oxathiazine series. SAR elucidation and optimization in regard to metabolic stability led to monocyclic tetramethyloxathiazines as exemplified by compound 21g.

Organizational Affiliation

Sanofi Deutschland GmbH, R&D, Industriepark Höchst, 65926 Frankfurt am Main, Germany.

Macromolecule Content

Total Structure Weight: 63.52 kDa
Atom Count: 4,496
Modelled Residue Count: 530
Deposited Residue Count: 552
Unique protein chains: 1

Macromolecules

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(by identity cutoff) | 3D Structure

Entity ID: 1
Molecule	Chains	Sequence Length	Organism	Details	Image
Corticosteroid 11-beta-dehydrogenase isozyme 1	A, B	276	Mus musculus	Mutation(s): 0 Gene Names: Hsd11b1, Hsd11 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 F [auth A] SDF format, chain I [auth B] MOL2 format, chain F [auth A] MOL2 format, chain I [auth B] mmCIF format, chain F [auth A] mmCIF format, chain I [auth B]	F [auth A], I [auth B]	NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₃₀ N₇ O₁₇ P₃ ACFIXJIJDZMPPO-NNYOXOHSSA-N		Interactions Focus chain F [auth A] Focus chain I [auth B] Interactions & Density Focus chain F [auth A] Focus chain I [auth B]
SFF Query on SFF Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain G [auth B] MOL2 format, chain C [auth A] MOL2 format, chain G [auth B] mmCIF format, chain C [auth A] mmCIF format, chain G [auth B]	C [auth A], G [auth B]	(4aS,8aR)-N-cyclohexyl-4a,5,6,7,8,8a-hexahydro-4,1,2-benzoxathiazin-3-amine 1,1-dioxide C₁₃ H₂₂ N₂ O₃ S ZMDVQNCMHSXAPA-NWDGAFQWSA-N		Interactions Focus chain C [auth A] Focus chain G [auth B] Interactions & Density Focus chain C [auth A] Focus chain G [auth B]
SO4 Query on SO4 Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain E [auth A] SDF format, chain H [auth B] MOL2 format, chain D [auth A] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B] mmCIF format, chain D [auth A] mmCIF format, chain E [auth A] mmCIF format, chain H [auth B]	D [auth A], E [auth A], H [auth B]	SULFATE ION O₄ S QAOWNCQODCNURD-UHFFFAOYSA-L		Interactions Focus chain D [auth A] Focus chain E [auth A] Focus chain H [auth B] Interactions & Density Focus chain D [auth A] Focus chain E [auth A] Focus chain H [auth B]

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.21 Å
R-Value Free: 0.208
R-Value Work: 0.166
R-Value Observed: 0.168
Space Group: C 2 2 2₁

Unit Cell:

Length ( Å )	Angle ( ˚ )
a = 133.864	α = 90
b = 137.333	β = 90
c = 70.557	γ = 90

Software Package:

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

Structure Validation

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Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-04-09

Deposition Author(s):

Loenze, P.

Schimanski-Breves, S.

Vonderheyden, C.

Engel, C.K.

Revision History (Full details and data files)

Version 1.0: 2014-04-09
Type: Initial release
Version 1.1: 2023-09-20
Changes: Data collection, Database references, Derived calculations, Refinement description