4GJA
Crystal structure of renin in complex with NVP-AYL747 (compound 5)
Summary for 4GJA
| Entry DOI | 10.2210/pdb4gja/pdb |
| Related | 4GJ8 4GJ9 4GJB 4GJC 4GJD |
| Descriptor | Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, (3S,5R)-N-(2,2-diphenylethyl)-5-{[(4-methylphenyl)sulfonyl]amino}piperidine-3-carboxamide, ... (5 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 | 76219.86 |
| Authors | Ostermann, N.,Zink, F.,Kroemer, M. (deposition date: 2012-08-09, release date: 2013-02-13, Last modification date: 2024-11-06) |
| 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 Cited by 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: 23360239DOI: 10.1021/jm301706j PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.6 Å) |
Structure validation
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