3IEJ

Pyrazole-based Cathepsin S Inhibitors with Arylalkynes as P1 Binding Elements

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.191 

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Literature

Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements.

Ameriks, M.K., Axe, F.U., Bembenek, S.D., Edwards, J.P., Gu, Y., Karlsson, L., Randal, M., Sun, S., Thurmond, R.L., Zhu, J.

(2009) Bioorg Med Chem Lett 19: 6131-6134

  • DOI: https://doi.org/10.1016/j.bmcl.2009.09.014
  • Primary Citation of Related Structures:  
    3IEJ

  • PubMed Abstract: 

    A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC50=40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme.

    • Organizational Affiliation: 

    Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA. mameriks@its.jnj.com


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Cathepsin S
A, B
222Homo sapiensMutation(s): 1 
Gene Names: CTSS
EC: 3.4.22.27
UniProt & NIH Common Fund Data Resources
Find proteins for P25774 (Homo sapiens)
Explore P25774 
Go to UniProtKB:  P25774
PHAROS:  P25774
GTEx:  ENSG00000163131 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP25774
Sequence Annotations
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  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
599
Query on 599
Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]		2-[3-{4-chloro-3-[(4-chlorophenyl)ethynyl]phenyl}-1-(3-morpholin-4-ylpropyl)-1,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridin-5-yl]-2-oxoethanol
C29 H30 Cl2 N4 O3
IWTCFPKHJADUJG-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
599 BindingDB:  3IEJ IC50: 220 (nM) from 1 assay(s)
PDBBind:  3IEJ IC50: 220 (nM) from 1 assay(s)
Binding MOAD:  3IEJ IC50: 220 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.18 Å
  • R-Value Free: 0.263 
  • R-Value Work: 0.187 
  • R-Value Observed: 0.191 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 113.264α = 90
b = 37.192β = 108.59
c = 105.863γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2009-10-06 
    • Deposition Author(s): Bembenek, S.

Revision History  (Full details and data files)

  • Version 1.0: 2009-10-06
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-13
    Changes: Database references, Derived calculations