5ABW

Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases

5ABW の概要

• エントリーDOI: 10.2210/pdb5abw/pdb
• 分子名称: NEUTROPHIL ELASTASE, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-[alpha-L-fucopyranose-(1-6)]2-acetamido-2-deoxy-beta-D-glucopyranose, 1-(3-CHLOROPHENYL)-5-(3,5-DIMETHYLISOXAZOL-4-YL)-6-METHYL-N-[4-(METHYLSULFONYL)BENZYL]-2-OXO-1,2-DIHYDROPYRIDINE-3-CARBOXAMIDE, ... (5 entities in total)
• 機能のキーワード: trypsin family fold, protease, hydrolase, hydrolase-inhibitor complex
• 由来する生物種: HOMO SAPIENS (HUMAN)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 24521.89

構造登録者

von Nussbaum, F.,Li, V.M.,Schaefer, M. (登録日: 2015-08-10, 公開日: 2015-08-19, 最終更新日: 2024-11-13)

主引用文献

von Nussbaum, F.,Li, V.M.
Neutrophil elastase inhibitors for the treatment of (cardio)pulmonary diseases: Into clinical testing with pre-adaptive pharmacophores.
Bioorg. Med. Chem. Lett., 25:4370-4381, 2015

PubMed Abstract: Alpha-1 antitrypsin deficiency is linked with an increased risk of suffering from lung emphysema. This discovery from the 1960s led to the development of the protease-antiprotease (im)balance hypothesis: Overshooting protease concentrations, especially high levels of elastase were deemed to have an destructive effect on lung tissue. Consequently, it was postulated that efficient elastase inhibitors could alleviate the situation in patients. However, despite intensive drug discovery efforts, even five decades later, no neutrophil elastase inhibitors are available for a disease-modifying treatment of (cardio)pulmonary diseases such as chronic obstructive pulmonary disease. Here, we critically review the attempts to develop effective human neutrophil elastase inhibitors while strongly focussing on recent developments. On purpose and with perspective distortion we focus on recent developments. One aim of this review is to classify the known HNE inhibitors into several generations, according to their binding modes. In general, there seem to be three major challenges in the development of suitable elastase inhibitors: (1) assuring sufficient potency, (2) securing selectivity, and (3) achieving metabolic stability especially under pathophysiological conditions. Impressive achievements have been made since 2001 with the identification of potent nonreactive, reversible small molecule inhibitors. The most modern inhibitors bind HNE via an induced fit with a frozen bioactive conformation that leads to a significant boost in potency, selectivity, and stability ('pre-adaptive pharmacophores'). These 5th generation inhibitors might succeed in re-establishing the protease-antiprotease balance in patients for the first time.

PubMed: 26358162
DOI: 10.1016/j.bmcl.2015.08.049

実験手法

X-RAY DIFFRACTION (1.6 Å)