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PDBsum entry 3g6z

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protein ligands Protein-protein interface(s) links
Hydrolase PDB id
3g6z
Jmol
Contents
Protein chain
337 a.a. *
Ligands
A7T ×2
NAG ×2
NDG
Waters ×435
* Residue conservation analysis
PDB id:
3g6z
Name: Hydrolase
Title: Design and preparation of potent, non-peptidic, bioavailable inhibitors
Structure: Renin. Chain: a, b. Synonym: angiotensinogenase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: human embryonic kidney cell
Resolution:
2.00Å     R-factor:   0.198     R-free:   0.258
Authors: O.Bezencon,D.Bur,L.Prade,T.Weller,C.Boss,W.Fischli
Key ref: O.Bezençon et al. (2009). Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors. J Med Chem, 52, 3689-3702. PubMed id: 19358611 DOI: 10.1021/jm900022f
Date:
09-Feb-09     Release date:   30-Jun-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P00797  (RENI_HUMAN) -  Renin
Seq:
Struc:
406 a.a.
337 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Enzyme reactions 
   Enzyme class: E.C.3.4.23.15  - Renin.
[IntEnz]   [ExPASy]   [KEGG]   [BRENDA]
      Reaction: Cleaves Leu-|- bond in angiotensinogen to generate angiotensin I.
 Gene Ontology (GO) functional annotation 
  GO annot!
  Biological process     proteolysis   1 term 
  Biochemical function     aspartic-type endopeptidase activity     1 term  

 

 
DOI no: 10.1021/jm900022f J Med Chem 52:3689-3702 (2009)
PubMed id: 19358611  
 
 
Design and preparation of potent, nonpeptidic, bioavailable renin inhibitors.
O.Bezençon, D.Bur, T.Weller, S.Richard-Bildstein, L.Remen, T.Sifferlen, O.Corminboeuf, C.Grisostomi, C.Boss, L.Prade, S.Delahaye, A.Treiber, P.Strickner, C.Binkert, P.Hess, B.Steiner, W.Fischli.
 
  ABSTRACT  
 
Starting from known piperidine renin inhibitors, a new series of 3,9-diazabicyclo[3.3.1]nonene derivatives was rationally designed and prepared. Optimization of the positions 3, 6, and 7 of the diazabicyclonene template led to potent renin inhibitors. The substituents attached at the positions 6 and 7 were essential for the binding affinity of these compounds for renin. The introduction of a substituent attached at the position 3 did not modify the binding affinity but allowed the modulation of the ADME properties. Our efforts led to the discovery of compound (+)-26g that inhibits renin with an IC(50) of 0.20 nM in buffer and 19 nM in plasma. The pharmacokinetics properties of this and other similar compounds are discussed. Compound (+)-26g is well absorbed in rats and efficacious at 10 mg/kg in vivo.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21376648 A.H.Al-Nadaf, and M.O.Taha (2011).
Discovery of new renin inhibitory leads via sequential pharmacophore modeling, QSAR analysis, in silico screening and in vitro evaluation.
  J Mol Graph Model, 29, 843-864.  
21429746 R.Aspiotis, A.Chen, E.Cauchon, D.Dubé, J.P.Falgueyret, S.Gagné, M.Gallant, E.L.Grimm, R.Houle, H.Juteau, P.Lacombe, S.Laliberté, J.F.Lévesque, D.MacDonald, D.McKay, M.D.Percival, P.Roy, S.M.Soisson, and T.Wu (2011).
The discovery and synthesis of potent zwitterionic inhibitors of renin.
  Bioorg Med Chem Lett, 21, 2430-2436.  
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