4MZS

Mouse cathepsin s with covalent ligand (3S,4S)-1-[(2-CHLOROPHENYL)SULFONYL]-N-[(2E)-2-IMINOETHYL]-4-(MORPHOLIN-4-YLCARBONYL)PYRROLIDINE-3-CARBOXAMIDE


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.226 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Identification of potent and selective cathepsin S inhibitors containing different central cyclic scaffolds.

Hilpert, H.Mauser, H.Humm, R.Anselm, L.Kuehne, H.Hartmann, G.Gruener, S.Banner, D.W.Benz, J.Gsell, B.Kuglstatter, A.Stihle, M.Thoma, R.Sanchez, R.A.Iding, H.Wirz, B.Haap, W.

(2013) J Med Chem 56: 9789-9801

  • DOI: https://doi.org/10.1021/jm401528k
  • Primary Citation of Related Structures:  
    4BS5, 4BSQ, 4MZO, 4MZS

  • PubMed Abstract: 

    Starting from the weakly active dual CatS/K inhibitor 5, structure-based design supported by X-ray analysis led to the discovery of the potent and selective (>50,000-fold vs CatK) cyclopentane derivative 22 by exploiting specific ligand-receptor interactions in the S2 pocket of CatS. Changing the central cyclopentane scaffold to the analogous pyrrolidine derivative 57 decreased the enzyme as well as the cell-based activity significantly by 24- and 69-fold, respectively. The most promising scaffold identified was the readily accessible proline derivative (e.g., 79). This compound, with an appealing ligand efficiency (LE) of 0.47, included additional structural modifications binding in the S1 and S3 pockets of CatS, leading to favorable in vitro and in vivo properties. Compound 79 reduced IL-2 production in a transgenic DO10.11 mouse model of antigen presentation in a dose-dependent manner with an ED50 of 5 mg/kg.


  • Organizational Affiliation

    Discovery Chemistry, ‡Cardiovascular and Metabolic Diseases, §Discovery Technologies, ∥Drug Metabolism and Pharmacokinetics, ⊥Process Research and Synthesis, Pharma Research and Early Development (pRED), F. Hoffmann-La Roche Ltd. , Grenzacherstrasse 124, Basel CH-4070, Switzerland.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cathepsin S
A, B
225Mus musculusMutation(s): 1 
Gene Names: CtssCats
EC: 3.4.22.27
UniProt & NIH Common Fund Data Resources
Find proteins for O70370 (Mus musculus)
Explore O70370 
Go to UniProtKB:  O70370
IMPC:  MGI:107341
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO70370
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2EV
Query on 2EV

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(3S,4S)-1-[(2-chlorophenyl)sulfonyl]-N-[(2E)-2-iminoethyl]-4-(morpholin-4-ylcarbonyl)pyrrolidine-3-carboxamide
C18 H23 Cl N4 O5 S
PZXUNWUKBPZQOX-HASADGDUSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.85 Å
  • R-Value Free: 0.270 
  • R-Value Work: 0.224 
  • R-Value Observed: 0.226 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 36.542α = 90
b = 88.959β = 90
c = 120.941γ = 90
Software Package:
Software NamePurpose
RemDAqdata collection
PHASERphasing
BUSTERrefinement
XDSdata reduction
SCALAdata 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: 2014-08-20
    Type: Initial release
  • Version 1.1: 2017-11-15
    Changes: Refinement description
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description