4YH3

Crystal structure of human BRD4(1) in complex with 4-[(2E)-3-(4-methoxyphenyl)-2-phenylprop-2-enoyl]-3,4-dihydroquinoxalin-2(1H)-one (compound 19a)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.162 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a new chemical series of BRD4(1) inhibitors using protein-ligand docking and structure-guided design.

Duffy, B.C.Liu, S.Martin, G.S.Wang, R.Hsia, M.M.Zhao, H.Guo, C.Ellis, M.Quinn, J.F.Kharenko, O.A.Norek, K.Gesner, E.M.Young, P.R.McLure, K.G.Wagner, G.S.Lakshminarasimhan, D.White, A.Suto, R.K.Hansen, H.C.Kitchen, D.B.

(2015) Bioorg Med Chem Lett 25: 2818-2823

  • DOI: https://doi.org/10.1016/j.bmcl.2015.04.107
  • Primary Citation of Related Structures:  
    4YH3, 4YH4

  • PubMed Abstract: 

    Bromodomains are key transcriptional regulators that are thought to be druggable epigenetic targets for cancer, inflammation, diabetes and cardiovascular therapeutics. Of particular importance is the first of two bromodomains in bromodomain containing 4 protein (BRD4(1)). Protein-ligand docking in BRD4(1) was used to purchase a small, focused screening set of compounds possessing a large variety of core structures. Within this set, a small number of weak hits each contained a dihydroquinoxalinone ring system. We purchased other analogs with this ring system and further validated the new hit series and obtained improvement in binding inhibition. Limited exploration by new analog synthesis showed that the binding inhibition in a FRET assay could be improved to the low μM level making this new core a potential hit-to-lead series. Additionally, the predicted geometries of the initial hit and an improved analog were confirmed by X-ray co-crystallography with BRD4(1).


  • Organizational Affiliation

    Albany Molecular Research (AMRI), 26 Corporate Circle, PO Box 15098, Albany, NY 12212-5098, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4129Homo sapiensMutation(s): 0 
Gene Names: BRD4HUNK1
UniProt & NIH Common Fund Data Resources
Find proteins for O60885 (Homo sapiens)
Explore O60885 
Go to UniProtKB:  O60885
PHAROS:  O60885
GTEx:  ENSG00000141867 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO60885
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
Y80
Query on Y80

Download Ideal Coordinates CCD File 
B [auth A]4-[(2E)-3-(4-methoxyphenyl)-2-phenylprop-2-enoyl]-3,4-dihydroquinoxalin-2(1H)-one
C24 H20 N2 O3
WQITZMVRSQPEBE-HMMYKYKNSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
Y80 Binding MOAD:  4YH3 IC50: 2.60e+4 (nM) from 1 assay(s)
BindingDB:  4YH3 IC50: 2.60e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.160 
  • R-Value Observed: 0.162 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 37.936α = 90
b = 44.072β = 90
c = 78.161γ = 90
Software Package:
Software NamePurpose
HKL-2000data reduction
PDB_EXTRACTdata extraction
REFMACrefinement
DENZOdata reduction
SCALEPACKdata 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: 2016-01-13
    Type: Initial release
  • Version 1.1: 2017-11-22
    Changes: Database references, Derived calculations, Refinement description
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references