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.
Highlights
Aspartic proteases are a class of enzymes widely found in fungi, plants, vertebrates, as well as, e.g., in HIV retro-viruses
The aspartic protease renin plays a role in hypertensive action, cathepsin D in tumorigenesis, plasmepsins in the degradation of human hemoglobin, which is required by Plasmodium falciparum, the causative agent of malaria and pepsin in the hydrolysis of acid-denatured proteins
Owing to the high degree of similarity, it has served as the model enzyme for the identification of inhibitors of renin [2] and β-secretase [3] and has been used to elucidate the mechanism of aspartic proteases [4,5,6]
Summary
Aspartic proteases are a class of enzymes widely found in fungi, plants, vertebrates, as well as, e.g., in HIV retro-viruses. Owing to the high degree of similarity, it has served as the model enzyme for the identification of inhibitors of renin [2] and β-secretase [3] and has been used to elucidate the mechanism of aspartic proteases [4,5,6]. It is a robust enzyme, active at room temperature for more than 20 days, available in large quantities. We have used structure-based drug design (SBDD) [8,9,10], to optimize an acylhydrazone-based inhibitor of endothiapepsin
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