6R9U

Human Cyclophilin D in complex with fragment


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.26 Å
  • R-Value Free: 0.172 
  • R-Value Work: 0.149 

wwPDB Validation 3D Report Full Report



Literature

Discovery of novel Cyclophilin D inhibitors starting from three dimensional fragments with millimolar potencies.

Gradler, U.Schwarz, D.Blaesse, M.Leuthner, B.Johnson, T.L.Bernard, F.Jiang, X.Marx, A.Gilardone, M.Lemoine, H.Roche, D.Jorand-Lebrun, C.

(2019) Bioorg Med Chem Lett 29: 126717-126717

  • DOI: 10.1016/j.bmcl.2019.126717
  • Structures With Same Primary Citation

  • PubMed Abstract: 
  • Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basi ...

    Fragment-based screening by SPR enabled the discovery of chemical diverse fragment hits with millimolar binding affinities to the peptidyl-prolyl isomerase Cyclophilin D (CypD). The CypD protein crystal structures of 6 fragment hits provided the basis for subsequent medicinal chemistry optimization by fragment merging and linking yielding three different chemical series with either urea, oxalyl or amide linkers connecting millimolar fragments in the S1' and S2 pockets. We successfully improved the in vitro CypD potencies in the biochemical FP and PPIase assays and in the biophysical SPR binding assay from millimolar towards the low micromolar and submicromolar range by >1000-fold for some fragment derivatives. The initial SAR together with the protein crystal structures of our novel CypD inhibitors provide a suitable basis for further hit-to-lead optimization.


    Organizational Affiliation

    EMD Serono Research & Development Institute Inc., 45A Middlesex Turnpike, Billerica, MA 01821, USA.



Macromolecules

Find similar proteins by: Sequence  |  Structure

Entity ID: 1
MoleculeChainsSequence LengthOrganismDetails
Peptidyl-prolyl cis-trans isomerase F, mitochondrial
A
164Homo sapiensMutation(s): 1 
Gene Names: PPIFCYP3
EC: 5.2.1.8
Find proteins for P30405 (Homo sapiens)
Go to UniProtKB:  P30405
NIH Common Fund Data Resources
PHAROS  P30405
Small Molecules
Ligands 4 Unique
IDChainsName / Formula / InChI Key2D Diagram3D Interactions
JVQ
Query on JVQ

Download CCD File 
A
14-ethyl-4,6-dioxa-10,14-diazatricyclo[7.6.0.0^{3,7}]pentadeca-1(9),2,7-trien-13-one
C13 H16 N2 O3
LCKKANZPYFOBHG-UHFFFAOYSA-N
 Ligand Interaction
PG4
Query on PG4

Download CCD File 
A
TETRAETHYLENE GLYCOL
C8 H18 O5
UWHCKJMYHZGTIT-UHFFFAOYSA-N
 Ligand Interaction
PGE
Query on PGE

Download CCD File 
A
TRIETHYLENE GLYCOL
C6 H14 O4
ZIBGPFATKBEMQZ-UHFFFAOYSA-N
 Ligand Interaction
SO4
Query on SO4

Download CCD File 
A
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
 Ligand Interaction
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.26 Å
  • R-Value Free: 0.172 
  • R-Value Work: 0.149 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.964α = 90
b = 56.964β = 90
c = 114.661γ = 90
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
REFMACrefinement
MOLREPphasing

Structure Validation

View Full Validation Report



Entry History 

Deposition Data

  • Deposited Date: 2019-04-04 
  • Released Date: 2019-11-27 
  • Deposition Author(s): Graedler, U.

Revision History 

  • Version 1.0: 2019-11-27
    Type: Initial release