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Int. J. Mol. Sci. 2015, 16(8), 19184-19194; doi:10.3390/ijms160819184

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
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: John George Hardy
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)
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Abstract

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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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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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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