3NCZ

X-Ray Co-structure of Rho-Associated Protein Kinase (ROCK1) with a potent 2H-isoquinolin-1-one inhibitor

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.328 
  • R-Value Work: 0.255 
  • R-Value Observed: 0.259 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history. 


Literature

Substituted 2H-isoquinolin-1-ones as potent Rho-kinase inhibitors: Part 2, optimization for blood pressure reduction in spontaneously hypertensive rats.

Ginn, J.D., Bosanac, T., Chen, R., Cywin, C., Hickey, E., Kashem, M., Kerr, S., Kugler, S., Li, X., Prokopowicz, A., Schlyer, S., Smith, J.D., Turner, M.R., Wu, F., Young, E.R.

(2010) Bioorg Med Chem Lett 20: 5153-5156

  • DOI: https://doi.org/10.1016/j.bmcl.2010.07.014
  • Primary Citation of Related Structures:  
    3NCZ

  • PubMed Abstract: 

    Phenylglycine substituted isoquinolones 1 and 2 have previously been described as potent dual ROCK1/ROCK2 inhibitors. Here we describe the further SAR of this series to improve metabolic stability and rat oral exposure. Piperidine analog 20 which demonstrates sustained blood pressure normalization in an SHR blood pressure reduction model was identified through this effort.

    • Organizational Affiliation: 

    Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877, USA. john.Ginn@boehringer-ingelheim.com


Macromolecules
Find similar proteins by: 
(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Rho-associated protein kinase 1
A, B, C, D
415Homo sapiensMutation(s): 0 
Gene Names: ROCK1
EC: 2.7.11.1
UniProt & NIH Common Fund Data Resources
Find proteins for Q13464 (Homo sapiens)
Explore Q13464 
Go to UniProtKB:  Q13464
PHAROS:  Q13464
GTEx:  ENSG00000067900 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ13464
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
3NC PDBBind:  3NCZ IC50: 15 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 3.00 Å
  • R-Value Free: 0.328 
  • R-Value Work: 0.255 
  • R-Value Observed: 0.259 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 161.439α = 90
b = 80.863β = 117.22
c = 166.619γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
CNXrefinement
MAR345dtbdata collection
d*TREKdata reduction
d*TREKdata scaling
CNXphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2010-12-08 
    • Deposition Author(s): Li, X.

Revision History  (Full details and data files)

  • Version 1.0: 2010-12-08
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2019-07-17
    Changes: Data collection, Refinement description
  • Version 1.3: 2024-02-21
    Changes: Data collection, Database references, Derived calculations