6FO5

FIRST DOMAIN OF HUMAN BROMODOMAIN BRD4 IN COMPLEX WITH INHIBITOR #17

  • Classification: DNA BINDING PROTEIN
  • Organism(s): Homo sapiens
  • Expression System: Escherichia coli BL21
  • Mutation(s): No 

  • Deposited: 2018-02-06 Released: 2018-06-20 
  • Deposition Author(s): Raux, B., Betzi, S.
  • Funding Organization(s): Canceropole PACA Institut National du Cancer Conseil Regional PACA, Fondation FRM pour la Recherche Medicale, Agence Nationale de la Recherche (ANR), Integrated Structural Biology (FRISBI)

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.95 Å
  • R-Value Free: 0.154 
  • R-Value Work: 0.136 
  • R-Value Observed: 0.136 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Integrated Strategy for Lead Optimization Based on Fragment Growing: The Diversity-Oriented-Target-Focused-Synthesis Approach.

Hoffer, L.Voitovich, Y.V.Raux, B.Carrasco, K.Muller, C.Fedorov, A.Y.Derviaux, C.Amouric, A.Betzi, S.Horvath, D.Varnek, A.Collette, Y.Combes, S.Roche, P.Morelli, X.

(2018) J Med Chem 61: 5719-5732

  • DOI: https://doi.org/10.1021/acs.jmedchem.8b00653
  • Primary Citation of Related Structures:  
    6FNX, 6FO5

  • PubMed Abstract: 

    Over the past few decades, hit identification has been greatly facilitated by advances in high-throughput and fragment-based screenings. One major hurdle remaining in drug discovery is process automation of hit-to-lead (H2L) optimization. Here, we report a time- and cost-efficient integrated strategy for H2L optimization as well as a partially automated design of potent chemical probes consisting of a focused-chemical-library design and virtual screening coupled with robotic diversity-oriented de novo synthesis and automated in vitro evaluation. The virtual library is generated by combining an activated fragment, corresponding to the substructure binding to the target, with a collection of functionalized building blocks using in silico encoded chemical reactions carefully chosen from a list of one-step organic transformations relevant in medicinal chemistry. The proof of concept was demonstrated using the optimization of bromodomain inhibitors as a test case, leading to the validation of several compounds with improved affinity by several orders of magnitude.


  • Organizational Affiliation

    CRCM, CNRS, Inserm, Institut Paoli-Calmettes , Aix-Marseille University , 13009 Marseille , France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Bromodomain-containing protein 4127Homo 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 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
DZH
Query on DZH

Download Ideal Coordinates CCD File 
B [auth A]~{N}-[[4-[[7-ethyl-2,6-bis(oxidanylidene)purin-3-yl]methyl]phenyl]methyl]-2-oxidanylidene-1,3,4,5-tetrahydro-1-benzazepine-7-sulfonamide
C25 H26 N6 O5 S
GUZDPSZLHQZPSV-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
DZH Binding MOAD:  6FO5 Kd: 190 (nM) from 1 assay(s)
BindingDB:  6FO5 Kd: 190 (nM) from 1 assay(s)
IC50: min: 251, max: 283 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 0.95 Å
  • R-Value Free: 0.154 
  • R-Value Work: 0.136 
  • R-Value Observed: 0.136 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 44.284α = 90
b = 47.498β = 90
c = 58.468γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
XDSdata reduction
XDSdata scaling
Cootmodel building
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
Canceropole PACA Institut National du Cancer Conseil Regional PACAFrance--
Fondation FRM pour la Recherche MedicaleFrance--
Agence Nationale de la Recherche (ANR)FranceANR-15-CE18-0023
Integrated Structural Biology (FRISBI)FranceANR-10-INSB-05-01

Revision History  (Full details and data files)

  • Version 1.0: 2018-06-20
    Type: Initial release
  • Version 1.1: 2018-07-04
    Changes: Data collection, Database references
  • Version 1.2: 2018-07-25
    Changes: Data collection, Database references
  • Version 1.3: 2024-01-17
    Changes: Author supporting evidence, Data collection, Database references, Refinement description