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PDBsum entry 3q4b

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protein ligands metals Protein-protein interface(s) links
Hydrolase/hydrolase inhibitor PDB id
3q4b
Jmol
Contents
Protein chain
337 a.a.
Ligands
NAG
RX5 ×2
Metals
_CL ×6
Waters ×186
PDB id:
3q4b
Name: Hydrolase/hydrolase inhibitor
Title: Clinically useful alkyl amine renin inhibitors
Structure: Renin. Chain: a, b. Fragment: unp residues 70-406. Synonym: angiotensinogenase. Engineered: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: ren, renin. Expressed in: homo sapiens. Expression_system_taxid: 9606. Expression_system_cell_line: hek 293.
Resolution:
2.19Å     R-factor:   0.212     R-free:   0.263
Authors: Z.Wu,B.M.Mckeever
Key ref: L.Jia et al. (2011). Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility. ACS Med Chem Lett, 2, 747-751. PubMed id: 24900262 DOI: 10.1021/ml200137x
Date:
23-Dec-10     Release date:   30-Nov-11    
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/ml200137x ACS Med Chem Lett 2:747-751 (2011)
PubMed id: 24900262  
 
 
Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
L.Jia, R.D.Simpson, J.Yuan, Z.Xu, W.Zhao, S.Cacatian, C.M.Tice, J.Guo, A.Ishchenko, S.B.Singh, Z.Wu, B.M.McKeever, Y.Bukhtiyarov, J.A.Johnson, C.P.Doe, R.K.Harrison, G.M.McGeehan, L.W.Dillard, J.J.Baldwin, D.A.Claremon.
 
  ABSTRACT  
 
Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.