Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

Alwin M Hartman, Milon Mondal, Nedyalka Radeva, Gerhard Klebe, Anna K H Hirsch

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10 Citations (Scopus)
313 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)19184-94
Number of pages11
JournalInternational Journal of Molecular Sciences
Volume16
Issue number8
DOIs
Publication statusPublished - 14-Aug-2015

Keywords

  • HYDE SCORING FUNCTION
  • X-RAY
  • MEDICINAL CHEMISTRY
  • CATALYTIC MECHANISM
  • DRUG DESIGN
  • NEUTRON
  • PROTEINASES
  • DIFFRACTION
  • DISCOVERY
  • structure based drug design
  • INHIBITORS
  • aspartic protease endothiapepsin
  • molecular recognition

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