Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

Alwin M. Hartman; Anna K. H. Hirsch; Gerhard Klebe; John George Hardy; Milon Mondal; Nedyalka Radeva

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Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

机译：天冬氨酸蛋白酶内皮抑素抑制剂的基于结构的优化

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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.

机译：天冬氨酸蛋白酶是一类酶，在诸如疟疾（纤溶酶），阿尔茨海默氏病（β-分泌酶），真菌感染（分泌的天冬氨酸蛋白酶）和高血压（肾素）等多种疾病中起着致病作用。我们选择了内皮素胃蛋白酶作为此类酶的模型酶，用于一系列新的内皮素胃蛋白酶抑制剂的设计，制备和生化评估。在这里，我们通过使用基于结构的设计方法来优化酰胺-π相互作用，从而优化了由基于新结构的药物设计（SBDD）和DCC识别的命中。生化结果与SBDD一致。这些结果将为未来针对真实药物靶标的抑制剂的基于结构的优化提供有用的见识，并为分子识别提供见识。

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《International Journal of Molecular Sciences》 |2015年第8期|共11页
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Alwin M. Hartman; Anna K. H. Hirsch; Gerhard Klebe; John George Hardy; Milon Mondal; Nedyalka Radeva;
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1. Structure-Based Design of Inhibitors of the Aspartic Protease Endothiapepsin by Exploiting Dynamic Combinatorial Chemistry [J] . Milon Mondal, Nedyalka Radeva, Helene Koster Angewandte Chemie . 2014,第12期

机译：利用动态组合化学的基于结构的天冬氨酸蛋白酶胃蛋白酶抑制剂的设计
2. Structure-based thermodynamic design of peptide ligands: application to peptide inhibitors of the aspartic protease endothiapepsin. [J] . Luque I, Gomez J, Semo N, Proteins: Structure, Function, and Genetics . 1998,第1期

机译：肽配体的基于结构的热力学设计：应用于天冬氨酸蛋白酶内皮抑素的肽抑制剂。
3. Fragment Linking and Optimization of Inhibitors of the Aspartic Protease Endothiapepsin: Fragment-Based Drug Design Facilitated by Dynamic Combinatorial Chemistry [J] . Mondal Milon, Radeva Nedyalka, Fanlo-Virgos Hugo, Angewandte Chemie . 2016,第32期

机译：片段连接和天冬氨酸蛋白酶内皮蛋白酶抑制剂的优化：动态组合化学促进基于片段的药物设计。
4. Screenig of human aspartic protease inhibitor by using ptoato aspartic protease inhibitor gene probe [C] . Hidekatsu Maeda, Yuh-ichiroh Harada, Tsuyoshi Sakai The Fifth China-Japn joint symposium on enzyme engineering . 1998

机译：利用马铃薯天冬氨酸蛋白酶抑制剂基因探针筛选人天冬氨酸蛋白酶抑制剂
5. Design and synthesis of novel non-peptide inhibitors of aspartic proteases. [D] . Shah, Neerav M. 2003

机译：设计和合成天冬氨酸蛋白酶的新型非肽抑制剂。
6. Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin [O] . Alwin M. Hartman, Milon Mondal, Nedyalka Radeva, 2015

机译：天冬氨酸蛋白酶内皮抑素抑制剂的基于结构的优化
7. Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin [O] . Alwin M. Hartman, Milon Mondal, Nedyalka Radeva, 2015

机译：基于结构的天冬氨酸蛋白酶内皮肽素抑制剂的优化

Structure-Based Optimization of Inhibitors of the Aspartic Protease Endothiapepsin

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