4GJ7

Crystal structure of renin in complex with NVP-BCA079 (compound 12a)

Summary for 4GJ7

• Entry DOI: 10.2210/pdb4gj7/pdb
• Related: 4GJ5 4GJ6
• Descriptor: Renin, 2-acetamido-2-deoxy-beta-D-glucopyranose, N-{[(3S,4S)-4-benzylpyrrolidin-3-yl]methyl}-4-methoxy-3-(3-methoxypropoxy)-N-(propan-2-yl)benzamide, ... (5 entities in total)
• Functional Keywords: renin inhibitor, pharmacophore search, trans-3, 4-disubstituted pyrrolidine, 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: 75981.70

Authors

Ostermann, N.,Zink, F.,Kroemer, M. (deposition date: 2012-08-09, release date: 2013-03-06, Last modification date: 2024-11-20)

Primary citation

Lorthiois, E.,Breitenstein, W.,Cumin, F.,Ehrhardt, C.,Francotte, E.,Jacoby, E.,Ostermann, N.,Sellner, H.,Kosaka, T.,Webb, R.L.,Rigel, D.F.,Hassiepen, U.,Richert, P.,Wagner, T.,Maibaum, J.
The Discovery of Novel Potent trans-3,4-Disubstituted Pyrrolidine Inhibitors of the Human Aspartic Protease Renin from in Silico Three-Dimensional (3D) Pharmacophore Searches.
J.Med.Chem., 56:2207-2217, 2013

PubMed Abstract: The small-molecule trans-3,4-disubstituted pyrrolidine 6 was identified from in silico three-dimensional (3D) pharmacophore searches based on known X-ray structures of renin-inhibitor complexes and demonstrated to be a weakly active inhibitor of the human enzyme. The unexpected binding mode of the more potent enantiomer (3S,4S)-6a in an extended conformation spanning the nonprime and S1' pockets of the recombinant human (rh)-renin active site was elucidated by X-ray crystallography. Initial structure-activity relationship work focused on modifications of the hydrophobic diphenylamine portion positioned in S1 and extending toward the S2 pocket. Replacement with an optimized P3-P1 pharmacophore interacting to the nonsubstrate S3(sp) cavity eventually resulted in significantly improved in vitro potency and selectivity. The prototype analogue (3S,4S)-12a of this new class of direct renin inhibitors exerted blood pressure lowering effects in a hypertensive double-transgenic rat model after oral administration.

PubMed: 23425156
DOI: 10.1021/jm3017078

Experimental method

X-RAY DIFFRACTION (2.8 Å)