2I4Q

Human renin/PF02342674 complex


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.230 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Rational design of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as small molecule renin inhibitors.

Powell, N.A.Ciske, F.L.Cai, C.Holsworth, D.D.Mennen, K.Van Huis, C.A.Jalaie, M.Day, J.Mastronardi, M.McConnell, P.Mochalkin, I.Zhang, E.Ryan, M.J.Bryant, J.Collard, W.Ferreira, S.Gu, C.Collins, R.Edmunds, J.J.

(2007) Bioorg Med Chem 15: 5912-5949

  • DOI: https://doi.org/10.1016/j.bmc.2007.05.069
  • Primary Citation of Related Structures:  
    2I4Q

  • PubMed Abstract: 

    We report the design and synthesis of a series of 6-(2,4-diaminopyrimidinyl)-1,4-benzoxazin-3-ones as orally bioavailable small molecule inhibitors of renin. Compounds with a 2-methyl-2-aryl substitution pattern exhibit potent renin inhibition and good permeability, solubility, and metabolic stability. Oral bioavailability was found to be dependent on metabolic clearance and cellular permeability, and was optimized through modulation of the sidechain that binds in the S3(sp) subsite.


  • Organizational Affiliation

    Pfizer Global Research & Development, Michigan Laboratories, Ann Arbor, MI 48105, USA. powellns@netzero.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Renin
A, B
336Homo sapiensMutation(s): 0 
Gene Names: REN
EC: 3.4.23.15
UniProt & NIH Common Fund Data Resources
Find proteins for P00797 (Homo sapiens)
Explore P00797 
Go to UniProtKB:  P00797
PHAROS:  P00797
GTEx:  ENSG00000143839 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00797
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
UA4
Query on UA4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
(2S)-6-(2,4-DIAMINO-6-ETHYLPYRIMIDIN-5-YL)-2-(3,5-DIFLUOROPHENYL)-4-(3-METHOXYPROPYL)-2-METHYL-2H-1,4-BENZOXAZIN-3(4H)-ONE
C25 H27 F2 N5 O3
UAXNNGUDPWZOKX-VWLOTQADSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
UA4 BindingDB:  2I4Q IC50: min: 7, max: 7.1 (nM) from 2 assay(s)
-TΔS: -1.54e+0 (kJ/mol) from 1 assay(s)
ΔG: -3.87e+1 (kJ/mol) from 1 assay(s)
Binding MOAD:  2I4Q IC50: 7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.261 
  • R-Value Work: 0.229 
  • R-Value Observed: 0.230 
  • Space Group: P 21 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 141.898α = 90
b = 141.898β = 90
c = 141.898γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
PDB_EXTRACTdata extraction
ADSCdata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2006-10-24
    Type: Initial release
  • Version 1.1: 2008-05-01
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance