4P38

Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with AZD8329

PDB DOI: https://doi.org/10.2210/pdb4P38/pdb

Classification: OXIDOREDUCTASE/OXIDOREDUCTASE INHIBITOR
Organism(s): Homo sapiens
Expression System: Escherichia coli
Mutation(s): No

Deposited: 2014-03-06 Released: 2014-04-30
Deposition Author(s): Ogg, D., Hargreaves, D., Gerhardt, S.

Experimental Data Snapshot

Method: X-RAY DIFFRACTION
Resolution: 2.80 ?
R-Value Free: 0.272
R-Value Work: 0.227
R-Value Observed: 0.229

wwPDB Validation 3D Report Full Report

Ligand Structure Quality Assessment

This is version 1.3 of the entry. See complete history.

Literature

Novel acidic 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).

Scott, J.S., deSchoolmeester, J., Kilgour, E., Mayers, R.M., Packer, M.J., Hargreaves, D., Gerhardt, S., Ogg, D.J., Rees, A., Selmi, N., Stocker, A., Swales, J.G., Whittamore, P.R.

(2012) J Med Chem 55: 10136-10147

PubMed: 23088558 Search on PubMed
DOI: https://doi.org/10.1021/jm301252n
Primary Citation of Related Structures:
4P38

PubMed Abstract:
Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.

Organizational Affiliation

Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca Mereside , Alderley Park, Macclesfield, Cheshire, SK10?4TG, United Kingdom. jamie.scott@astrazeneca.com

Macromolecule Content

Total Structure Weight: 60.84 kDa
Atom Count: 4,266
Modelled Residue Count: 528
Deposited Residue Count: 530
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	265	Homo sapiens	Mutation(s): 0 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 3 Unique
ID	Chains	Name / Formula / InChI Key	2D Diagram	3D Interactions
NDP Query on NDP Download Ideal Coordinates CCD File SDF format, chain C [auth A] SDF format, chain F [auth B] MOL2 format, chain C [auth A] MOL2 format, chain F [auth B] mmCIF format, chain C [auth A] mmCIF format, chain F [auth B]	C [auth A], F [auth B]	NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE C₂₁ H₃₀ N₇ O₁₇ P₃ ACFIXJIJDZMPPO-NNYOXOHSSA-N		Interactions Focus chain C [auth A] Focus chain F [auth B] Interactions & Density Focus chain C [auth A] Focus chain F [auth B]
21T Query on 21T Download Ideal Coordinates CCD File SDF format, chain D [auth A] SDF format, chain G [auth B] MOL2 format, chain D [auth A] MOL2 format, chain G [auth B] mmCIF format, chain D [auth A] mmCIF format, chain G [auth B]	D [auth A], G [auth B]	4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid C₂₅ H₃₁ N₃ O₃ XWBXJBSVYVJAMZ-RCQAVAAASA-N		Interactions Focus chain D [auth A] Focus chain G [auth B] Interactions & Density Focus chain D [auth A] Focus chain G [auth B]
CL Query on CL Download Ideal Coordinates CCD File SDF format, chain E [auth A] SDF format, chain H [auth B] MOL2 format, chain E [auth A] MOL2 format, chain H [auth B] mmCIF format, chain E [auth A] mmCIF format, chain H [auth B]	E [auth A], H [auth B]	CHLORIDE ION Cl VEXZGXHMUGYJMC-UHFFFAOYSA-M		Interactions Focus chain E [auth A] Focus chain H [auth B] Interactions & Density Focus chain E [auth A] Focus chain H [auth B]

Binding Affinity Annotations
ID	Source	Binding Affinity
21T	BindingDB: 4P38	IC50: min: 2, max: 9 (nM) from 2 assay(s)

Experimental Data & Validation

Experimental Data

Method: X-RAY DIFFRACTION
Resolution: 2.80 ?
R-Value Free: 0.272
R-Value Work: 0.227
R-Value Observed: 0.229
Space Group: P 3₁ 2 1

Unit Cell:

Length ( ? )	Angle ( ? )
a = 103.516	α = 90
b = 103.516	β = 90
c = 134.78	γ = 120

Software Package:

Software Name	Purpose
BUSTER	refinement
d*TREK	data scaling
CrystalClear	data collection
AMoRE	phasing

Structure Validation

View Full Validation Report

Ligand Structure Quality Assessment

Entry History

Deposition Data

Released Date: 2014-04-30

Deposition Author(s):

Ogg, D.

Hargreaves, D.

Gerhardt, S.

Revision History (Full details and data files)

Version 1.0: 2014-04-30
Type: Initial release
Version 1.1: 2014-11-12
Changes: Structure summary
Version 1.2: 2017-11-01
Changes: Author supporting evidence, Database references, Derived calculations, Other, Refinement description, Source and taxonomy
Version 1.3: 2024-02-28
Changes: Data collection, Database references, Refinement description