4GJ8

Crystal structure of renin in complex with PKF909-724 (compound 3)

Summary for 4GJ8

• Entry DOI: 10.2210/pdb4gj8/pdb
• Related: 4GJ9 4GJA 4GJB 4GJC 4GJD
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, (2S)-1-(pyrrolidin-1-yl)-3-(9H-thioxanthen-9-yl)propan-2-ol, ... (6 entities in total)
• Functional Keywords: renin inhibitor, fragment based screening, 3, 5-disubstituted piperidines, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Secreted: P00797
• Total number of polymer chains: 2
• Total formula weight: 76144.96

Authors

Ostermann, N.,Zink, F.,Kroemer, M. (deposition date: 2012-08-09, release date: 2013-02-13, Last modification date: 2023-09-13)

Primary citation

Ostermann, N.,Ruedisser, S.,Ehrhardt, C.,Breitenstein, W.,Marzinzik, A.,Jacoby, E.,Vangrevelinghe, E.,Ottl, J.,Klumpp, M.,Hartwieg, J.C.,Cumin, F.,Hassiepen, U.,Trappe, J.,Sedrani, R.,Geisse, S.,Gerhartz, B.,Richert, P.,Francotte, E.,Wagner, T.,Kromer, M.,Kosaka, T.,Webb, R.L.,Rigel, D.F.,Maibaum, J.,Baeschlin, D.K.
A novel class of oral direct Renin inhibitors: highly potent 3,5-disubstituted piperidines bearing a tricyclic p3-p1 pharmacophore.
J.Med.Chem., 56:2196-2206, 2013

PubMed 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.

PubMed: 23360239
DOI: 10.1021/jm301706j

Experimental method

X-RAY DIFFRACTION (2.5 Å)