4K1L

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

PDB DOI: https://doi.org/10.2210/pdb4K1L/pdb

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

Deposited: 2013-04-05 Released: 2014-04-09
Deposition Author(s): Loenze, P., Schimanski-Breves, S., Von der Heyden, C., Engel, C.K.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 1.96 ?
R-Value Free: 0.202
R-Value Work: 0.167
R-Value Observed: 0.169

Starting Model: experimental
View more details

wwPDB Validation 3D Report Full Report

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 11?-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 H?chst, 65926 Frankfurt am Main, Germany.

Macromolecule Content

Total Structure Weight: 131.47 kDa
Atom Count: 9,120
Modelled Residue Count: 1,056
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]
SFF Query on SFF 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]	(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 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: 1.96 ?
R-Value Free: 0.202
R-Value Work: 0.167
R-Value Observed: 0.169
Space Group: P 1 2₁ 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 57.361	α = 90
b = 150.941	β = 93.79
c = 74.169	γ = 90

Software Package:

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

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-04-09

Deposition Author(s):

Loenze, P.

Schimanski-Breves, S.

Von der Heyden, 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