5I4V

Discovery of novel, orally efficacious Liver X Receptor (LXR) beta agonists


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

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Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of a Novel, Orally Efficacious Liver X Receptor (LXR) beta Agonist.

Zheng, Y.Zhuang, L.Fan, K.Y.Tice, C.M.Zhao, W.Dong, C.Lotesta, S.D.Leftheris, K.Lindblom, P.R.Liu, Z.Shimada, J.Noto, P.B.Meng, S.Hardy, A.Howard, L.Krosky, P.Guo, J.Lipinski, K.Kandpal, G.Bukhtiyarov, Y.Zhao, Y.Lala, D.Van Orden, R.Zhou, J.Chen, G.Wu, Z.McKeever, B.M.McGeehan, G.M.Gregg, R.E.Claremon, D.A.Singh, S.B.

(2016) J Med Chem 59: 3264-3271

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b02029
  • Primary Citation of Related Structures:  
    5I4V

  • PubMed Abstract: 

    This article describes the application of Contour to the design and discovery of a novel, potent, orally efficacious liver X receptor β (LXRβ) agonist (17). Contour technology is a structure-based drug design platform that generates molecules using a context perceptive growth algorithm guided by a contact sensitive scoring function. The growth engine uses binding site perception and programmable growth capability to create drug-like molecules by assembling fragments that naturally complement hydrophilic and hydrophobic features of the protein binding site. Starting with a crystal structure of LXRβ and a docked 2-(methylsulfonyl)benzyl alcohol fragment (6), Contour was used to design agonists containing a piperazine core. Compound 17 binds to LXRβ with high affinity and to LXRα to a lesser extent, and induces the expression of LXR target genes in vitro and in vivo. This molecule served as a starting point for further optimization and generation of a candidate which is currently in human clinical trials for treating atopic dermatitis.


  • Organizational Affiliation

    Vitae Pharmaceuticals, Inc. , 502 W. Office Center Drive, Fort Washington, Pennsylvania 19034, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Oxysterols receptor LXR-beta,Nuclear receptor coactivator 2A,
C [auth E]
270Homo sapiensMutation(s): 6 
Gene Names: NR1H2LXRBNERUNRNCOA2BHLHE75SRC2TIF2
UniProt & NIH Common Fund Data Resources
Find proteins for P55055 (Homo sapiens)
Explore P55055 
Go to UniProtKB:  P55055
PHAROS:  P55055
GTEx:  ENSG00000131408 
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 GroupsQ15596P55055
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Retinoic acid receptor RXR-beta,Nuclear receptor coactivator 2B,
D [auth F]
255Homo sapiensMutation(s): 1 
Gene Names: RXRBNR2B2NCOA2BHLHE75SRC2TIF2
UniProt & NIH Common Fund Data Resources
Find proteins for P28702 (Homo sapiens)
Explore P28702 
Go to UniProtKB:  P28702
PHAROS:  P28702
GTEx:  ENSG00000204231 
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 GroupsQ15596P28702
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
67S
Query on 67S

Download Ideal Coordinates CCD File 
E [auth A],
F [auth E]
{2-[(2R)-4-[4-(hydroxymethyl)-3-(methylsulfonyl)phenyl]-2-(propan-2-yl)piperazin-1-yl]-4-(trifluoromethyl)pyrimidin-5-yl}methanol
C21 H27 F3 N4 O4 S
FPVIRRAMNBCEDK-KRWDZBQOSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
67S BindingDB:  5I4V Ki: min: 1.3, max: 3 (nM) from 2 assay(s)
EC50: min: 4, max: 21 (nM) from 3 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.248 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 68.637α = 90
b = 101.221β = 90
c = 143.274γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

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Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-06-29
    Type: Initial release
  • Version 1.1: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description