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Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

Hartman, A. M., Mondal, M., Radeva, N., Klebe, G. & Hirsch, A. K. H., 14-Aug-2015, In : International Journal of Molecular Sciences. 16, 8, p. 19184-94 11 p.

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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
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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