5NI5

Ligand complex of RORg LBD


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.225 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Potent and Orally Bioavailable Inverse Agonists of ROR gamma t Resulting from Structure-Based Design.

Narjes, F.Xue, Y.von Berg, S.Malmberg, J.Llinas, A.Olsson, R.I.Jirholt, J.Grindebacke, H.Leffler, A.Hossain, N.Lepisto, M.Thunberg, L.Leek, H.Aagaard, A.McPheat, J.Hansson, E.L.Back, E.Tangefjord, S.Chen, R.Xiong, Y.Hongbin, G.Hansson, T.G.

(2018) J Med Chem 61: 7796-7813

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00783
  • Primary Citation of Related Structures:  
    5NI5, 5NI7, 5NI8, 5NIB, 6ESN, 6FGQ

  • PubMed Abstract: 

    Retinoic acid receptor related orphan receptor γt (RORγt), has been identified as the master regulator of T H 17-cell function and development, making it an attractive target for the treatment of autoimmune diseases by a small-molecule approach. Herein, we describe our investigations on a series of 4-aryl-thienyl acetamides, which were guided by insights from X-ray cocrystal structures. Efforts in targeting the cofactor-recruitment site from the 4-aryl group on the thiophene led to a series of potent binders with nanomolar activity in a primary human-T H 17-cell assay. The observation of a DMSO molecule binding in a subpocket outside the LBD inspired the introduction of an acetamide into the benzylic position of these compounds. Hereby, a hydrogen-bond interaction of the introduced acetamide oxygen with the backbone amide of Glu379 was established. This greatly enhanced the cellular activity of previously weakly cell-active compounds. The best compounds combined potent inhibition of IL-17 release with favorable PK in rodents, with compound 32 representing a promising starting point for future investigations.


  • Organizational Affiliation

    Early Product Development , Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca , Gothenburg , SE-43183 Mölndal , Sweden.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor ROR-gamma288Homo sapiensMutation(s): 0 
Gene Names: RORCNR1F3RORGRZRG
UniProt & NIH Common Fund Data Resources
Find proteins for P51449 (Homo sapiens)
Explore P51449 
Go to UniProtKB:  P51449
PHAROS:  P51449
GTEx:  ENSG00000143365 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP51449
Sequence Annotations
Expand
  • Reference Sequence

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
tethered SRC2-2 peptideB [auth C]15Homo sapiensMutation(s): 0 
UniProt & NIH Common Fund Data Resources
Find proteins for Q15596 (Homo sapiens)
Explore Q15596 
Go to UniProtKB:  Q15596
PHAROS:  Q15596
GTEx:  ENSG00000140396 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ15596
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
8YB
Query on 8YB

Download Ideal Coordinates CCD File 
C [auth A]~{N}-[4-(3-chlorophenyl)-5-(2-chlorophenyl)carbonyl-1,3-thiazol-2-yl]-2-(4-ethylsulfonylphenyl)ethanamide
C26 H20 Cl2 N2 O4 S2
GRWNPFJXINLSNF-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
D [auth A]SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
8YB BindingDB:  5NI5 Ki: 40 (nM) from 1 assay(s)
IC50: min: 7.9, max: 200 (nM) from 9 assay(s)
EC50: min: 8, max: 158 (nM) from 3 assay(s)
Binding MOAD:  5NI5 IC50: 9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.265 
  • R-Value Work: 0.223 
  • R-Value Observed: 0.225 
  • Space Group: P 41 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 62.31α = 90
b = 62.31β = 90
c = 158.64γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
XDSdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2018-08-22
    Type: Initial release
  • Version 1.1: 2018-10-24
    Changes: Data collection, Database references
  • Version 1.2: 2024-01-17
    Changes: Data collection, Database references, Derived calculations, Refinement description