4GJD: Crystal Structure Of Renin In Complex With Nvp-bgq311 (compound 12)

Citation:
Abstract
A small library of fragments comprising putative recognition motifs for the catalytic dyad of aspartic proteases was generated by in silico similarity searches within the corporate compound deck based on rh-renin active site docking and scoring filters. Subsequent screening by NMR identified the low-affinity hits 3 and 4 as competitive active site binders, which could be shown by X-ray crystallography to bind to the hydrophobic S3-S1 pocket of rh-renin. As part of a parallel multiple hit-finding approach, the 3,5-disubstituted piperidine (rac)-5 was discovered by HTS using a enzymatic assay. X-ray crystallography demonstrated the eutomer (3S,5R)-5 to be a peptidomimetic inhibitor binding to a nonsubstrate topography of the rh-renin prime site. The design of the potent and selective (3S,5R)-12 bearing a P3(sp)-tethered tricyclic P3-P1 pharmacophore derived from 3 is described. (3S,5R)-12 showed oral bioavailability in rats and demonstrated blood pressure lowering activity in the double-transgenic rat model.
PDB ID: 4GJDDownload
MMDB ID: 107608
PDB Deposition Date: 2012/8/9
Updated in MMDB: 2013/04
Experimental Method:
x-ray diffraction
Resolution: 2.65  Å
Source Organism:
Similar Structures:
Biological Unit for 4GJD: monomeric; determined by author
Molecular Components in 4GJD
Label Count Molecule
Protein (1 molecule)
1
Renin(Gene symbol: REN)
Molecule annotation
Chemicals (3 molecules)
1
1
2
1
3
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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