4AZ0

crystal structure of cathepsin a, complexed with 8a.

Summary for 4AZ0

• Entry DOI: 10.2210/pdb4az0/pdb
• Related: 1IVY 4AZ3
• Descriptor: LYSOSOMAL PROTECTIVE PROTEIN 32 KDA CHAIN, LYSOSOMAL PROTECTIVE PROTEIN 20 KDA CHAIN, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (6 entities in total)
• Functional Keywords: hydrolase, drug discovery, cardiovascular drug
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 53754.11

Authors

Ruf, S.,Buning, C.,Schreuder, H.,Horstick, G.,Linz, W.,Olpp, T.,Pernerstorfer, J.,Hiss, K.,Kroll, K.,Kannt, A.,Kohlmann, M.,Linz, D.,Huebschle, T.,Ruetten, H.,Wirth, K.,Schmidt, T.,Sadowski, T. (deposition date: 2012-06-22, release date: 2012-09-26, Last modification date: 2024-11-06)

Primary citation

Ruf, S.,Buning, C.,Schreuder, H.,Horstick, G.,Linz, W.,Olpp, T.,Pernerstorfer, J.,Hiss, K.,Kroll, K.,Kannt, A.,Kohlmann, M.,Linz, D.,Hubschle, T.,Rutten, H.,Wirth, K.,Schmidt, T.,Sadowski, T.
Novel Beta-Amino Acid Derivatives as Inhibitors of Cathepsin A.
J.Med.Chem., 55:7636-, 2012

PubMed Abstract: Cathepsin A (CatA) is a serine carboxypeptidase distributed between lysosomes, cell membrane, and extracellular space. Several peptide hormones including bradykinin and angiotensin I have been described as substrates. Therefore, the inhibition of CatA has the potential for beneficial effects in cardiovascular diseases. Pharmacological inhibition of CatA by the natural product ebelactone B increased renal bradykinin levels and prevented the development of salt-induced hypertension. However, so far no small molecule inhibitors of CatA with oral bioavailability have been described to allow further pharmacological profiling. In our work we identified novel β-amino acid derivatives as inhibitors of CatA after a HTS analysis based on a project adapted fragment approach. The new inhibitors showed beneficial ADME and pharmacokinetic profiles, and their binding modes were established by X-ray crystallography. Further investigations led to the identification of a hitherto unknown pathophysiological role of CatA in cardiac hypertrophy. One of our inhibitors is currently undergoing phase I clinical trials.

PubMed: 22861813
DOI: 10.1021/JM300663N

Experimental method

X-RAY DIFFRACTION (2.17 Å)