Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

International Journal of Molecular Sciences

Alwin M. Hartman²  Milon Mondal²  Nedyalka Radeva¹  Gerhard Klebe¹  Anna K. H. Hirsch² 

[1] Institute of Pharmaceutical Chemistry, Philipps-University Marburg, Marbacher Weg 6, 35032 Marburg, Germany; E-Mails:;Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands; E-Mails:

关键词: inhibitors;    aspartic protease endothiapepsin;    structure-based drug design;    molecular recognition;   

DOI  :  10.3390/ijms160819184

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.