5A0C

Crystal Structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor

5A0C の概要

• エントリーDOI: 10.2210/pdb5a0c/pdb
• 関連するPDBエントリー: 5A09 5A0A 5A0B
• 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, alpha-L-fucopyranose-(1-6)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 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: 2
• 化学式量合計: 50283.62

構造登録者

vonNussbaum, F.,Li, V.M.-J.,Allerheiligen, S.,Anlauf, S.,Baerfacker, L.,Bechem, M.,Delbeck, M.,Fitzgerald, M.F.,Gerisch, M.,Gielen-Haertwig, H.,Haning, H.,Karthaus, D.,Lang, D.,Lustig, K.,Meibom, D.,Mittendorf, J.,Rosentreter, U.,Schaefer, M.,Schaefer, S.,Schamberger, J.,Telan, L.A.,Tersteegen, A. (登録日: 2015-04-17, 公開日: 2015-08-19, 最終更新日: 2020-07-29)

主引用文献

von Nussbaum, F.,Li, V.M.,Allerheiligen, S.,Anlauf, S.,Barfacker, L.,Bechem, M.,Delbeck, M.,Fitzgerald, M.F.,Gerisch, M.,Gielen-Haertwig, H.,Haning, H.,Karthaus, D.,Lang, D.,Lustig, K.,Meibom, D.,Mittendorf, J.,Rosentreter, U.,Schafer, M.,Schafer, S.,Schamberger, J.,Telan, L.A.,Tersteegen, A.
Freezing the Bioactive Conformation to Boost Potency: The Identification of BAY 85-8501, a Selective and Potent Inhibitor of Human Neutrophil Elastase for Pulmonary Diseases.
ChemMedChem, 10:1163-1173, 2015

PubMed Abstract: Human neutrophil elastase (HNE) is a key protease for matrix degradation. High HNE activity is observed in inflammatory diseases. Accordingly, HNE is a potential target for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD), acute lung injury (ALI), acute respiratory distress syndrome (ARDS), bronchiectasis (BE), and pulmonary hypertension (PH). HNE inhibitors should reestablish the protease-anti-protease balance. By means of medicinal chemistry a novel dihydropyrimidinone lead-structure class was identified. Further chemical optimization yielded orally active compounds with favorable pharmacokinetics such as the chemical probe BAY-678. While maintaining outstanding target selectivity, picomolar potency was achieved by locking the bioactive conformation of these inhibitors with a strategically positioned methyl sulfone substituent. An induced-fit binding mode allowed tight interactions with the S2 and S1 pockets of HNE. BAY 85-8501 ((4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile) was shown to be efficacious in a rodent animal model related to ALI. BAY 85-8501 is currently being tested in clinical studies for the treatment of pulmonary diseases.

PubMed: 26083237
DOI: 10.1002/cmdc.201500131

実験手法

X-RAY DIFFRACTION (2.1 Å)