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Open AccessArticle

Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

1
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands
2
Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: John George Hardy
Int. J. Mol. Sci. 2015, 16(8), 19184-19194; https://doi.org/10.3390/ijms160819184
Received: 1 May 2015 / Revised: 27 June 2015 / Accepted: 6 July 2015 / Published: 14 August 2015
(This article belongs to the Special Issue Supramolecular Interactions)
Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer’s disease (β-secretase), fungal infections (secreted aspartic proteases), and hypertension (renin). We have chosen endothiapepsin as a model enzyme of this class of enzymes, for the design, preparation and biochemical evaluation of a new series of inhibitors of endothiapepsin. Here, we have optimized a hit, identified by de novo structure-based drug design (SBDD) and DCC, by using structure-based design approaches focusing on the optimization of an amide–π interaction. Biochemical results are in agreement with SBDD. These results will provide useful insights for future structure-based optimization of inhibitors for the real drug targets as well as insights into molecular recognition. View Full-Text
Keywords: inhibitors; aspartic protease endothiapepsin; structure-based drug design; molecular recognition inhibitors; aspartic protease endothiapepsin; structure-based drug design; molecular recognition
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MDPI and ACS Style

Hartman, A.M.; Mondal, M.; Radeva, N.; Klebe, G.; Hirsch, A.K.H. Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin. Int. J. Mol. Sci. 2015, 16, 19184-19194.

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