3WZ8

Endothiapepsin in complex with Gewald reaction-derived inhibitor (8)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.190 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Tracing binding modes in hit-to-lead optimization: chameleon-like poses of aspartic protease inhibitors

Kuhnert, M.Koster, H.Bartholomaus, R.Park, A.Y.Shahim, A.Heine, A.Steuber, H.Klebe, G.Diederich, W.E.

(2015) Angew Chem Int Ed Engl 54: 2849-2853

  • DOI: https://doi.org/10.1002/anie.201411206
  • Primary Citation of Related Structures:  
    3PSY, 3WZ6, 3WZ7, 3WZ8

  • PubMed Abstract: 

    Successful lead optimization in structure-based drug discovery depends on the correct deduction and interpretation of the underlying structure-activity relationships (SAR) to facilitate efficient decision-making on the next candidates to be synthesized. Consequently, the question arises, how frequently a binding mode (re)-validation is required, to ensure not to be misled by invalid assumptions on the binding geometry. We present an example in which minor chemical modifications within one inhibitor series lead to surprisingly different binding modes. X-ray structure determination of eight inhibitors derived from one core scaffold resulted in four different binding modes in the aspartic protease endothiapepsin, a well-established surrogate for e.g. renin and β-secretase. In addition, we suggest an empirical metrics that might serve as an indicator during lead optimization to qualify compounds as candidates for structural revalidation.


  • Organizational Affiliation

    Institut für Pharmazeutische Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 3, 35032 Marburg (Germany).


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Endothiapepsin330Cryphonectria parasiticaMutation(s): 0 
EC: 3.4.23.22
UniProt
Find proteins for P11838 (Cryphonectria parasitica)
Explore P11838 
Go to UniProtKB:  P11838
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP11838
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
IXV
Query on IXV

Download Ideal Coordinates CCD File 
B [auth A]N-benzyl-4-phenyl-2-[(N-phenyl-beta-alanyl)amino]thiophene-3-carboxamide
C27 H25 N3 O2 S
CDYLPAHZUJIEAN-UHFFFAOYSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
C [auth A]DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
D [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
IXV Binding MOAD:  3WZ8 Ki: 1500 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.45 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.190 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 45.61α = 90
b = 73.93β = 110.73
c = 54.19γ = 90
Software Package:
Software NamePurpose
MxCuBEdata collection
PHASERphasing
PHENIXrefinement
XDSdata reduction
XDSdata 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: 2015-08-05
    Type: Initial release
  • Version 1.1: 2023-11-08
    Changes: Data collection, Database references, Derived calculations, Refinement description