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Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.

ABSTRACT: Aspartic proteases are a class of enzymes that play a causative role in numerous diseases such as malaria (plasmepsins), Alzheimer's disease (?-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-? 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.

SUBMITTER: Hartman AM

PROVIDER: S-EPMC4581293 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin.

Hartman Alwin M AM Mondal Milon M Radeva Nedyalka N Klebe Gerhard G Hirsch Anna K H AK

International journal of molecular sciences 20150814 8

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 ...[more]

PMID: 26287174

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