4JPA

Mmp13 in complex with a piperazine hydantoin ligand


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.180 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Hydantoin based inhibitors of MMP13--discovery of AZD6605.

De Savi, C.Waterson, D.Pape, A.Lamont, S.Hadley, E.Mills, M.Page, K.M.Bowyer, J.Maciewicz, R.A.

(2013) Bioorg Med Chem Lett 23: 4705-4712

  • DOI: https://doi.org/10.1016/j.bmcl.2013.05.089
  • Primary Citation of Related Structures:  
    4JP4, 4JPA

  • PubMed Abstract: 

    Piperidine ether and aryl piperazine hydantoins are reported as potent inhibitors of MMP13. A medicinal chemistry campaign focused on replacing the reverse hydroxamate zinc binding group associated with historical inhibitors with a hydantoin zinc binding group then optimising MMP13 potency, solubility and DMPK properties whilst maintaining good selectivity over MMP14. A number of high quality candidates were progressed and following rat and dog safety evaluation, AZD6605 (3m) was identified as a candidate drug.


  • Organizational Affiliation

    Oncology Innovative Medicines, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA. chris.desavi2@astrazeneca.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Collagenase 3
A, B
173Homo sapiensMutation(s): 0 
Gene Names: MMP13
EC: 3.4.24
UniProt & NIH Common Fund Data Resources
Find proteins for P45452 (Homo sapiens)
Explore P45452 
Go to UniProtKB:  P45452
PHAROS:  P45452
GTEx:  ENSG00000137745 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP45452
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
AZ6
Query on AZ6

Download Ideal Coordinates CCD File 
H [auth A],
N [auth B]
3-[({2-[4-({[(4S)-4-methyl-2,5-dioxoimidazolidin-4-yl]methyl}sulfonyl)piperazin-1-yl]pyrimidin-5-yl}oxy)methyl]benzonitrile
C21 H23 N7 O5 S
PKCWEIUDUFDFAG-OAQYLSRUSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
C [auth A],
E [auth A],
I [auth B],
J [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CA
Query on CA

Download Ideal Coordinates CCD File 
D [auth A],
F [auth A],
K [auth B],
L [auth B]
CALCIUM ION
Ca
BHPQYMZQTOCNFJ-UHFFFAOYSA-N
NA
Query on NA

Download Ideal Coordinates CCD File 
G [auth A],
M [auth B]
SODIUM ION
Na
FKNQFGJONOIPTF-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
AZ6 Binding MOAD:  4JPA IC50: 3.3 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.00 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.177 
  • R-Value Observed: 0.180 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 134.771α = 90
b = 35.986β = 134.99
c = 101.492γ = 90
Software Package:
Software NamePurpose
SCALAdata scaling
AMoREphasing
REFMACrefinement
PDB_EXTRACTdata extraction
StructureStudiodata collection
DENZOdata reduction
SCALEPACKdata scaling
d*TREKdata 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: 2014-03-05
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Refinement description
  • Version 1.2: 2024-03-20
    Changes: Data collection, Database references, Derived calculations