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PDBsum entry 5a0c
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PDB id:
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Hydrolase
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Title:
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Crystal structure of human neutrophil elastase in complex with a dihydropyrimidone inhibitor
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Structure:
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Neutrophil elastase. Chain: a, b. Fragment: unp residues 30-247. Synonym: bone marrow serine protease, elastase-2, human leukocyte el astase, hle, medullasin, pmn elastase, elastase, hle, meduliasin, pmn elastase. Ec: 3.4.21.37
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Source:
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Homo sapiens. Human. Organism_taxid: 9606
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Resolution:
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2.10Å
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R-factor:
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0.166
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R-free:
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0.213
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Authors:
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F.Vonnussbaum,V.M.-J.Li,S.Allerheiligen,S.Anlauf,L.Baerfacker, M.Bechem,M.Delbeck,M.F.Fitzgerald,M.Gerisch,H.Gielen-Haertwig, H.Haning,D.Karthaus,D.Lang,K.Lustig,D.Meibom,J.Mittendorf, U.Rosentreter,M.Schaefer,S.Schaefer,J.Schamberger,L.A.Telan, A.Tersteegen
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Key ref:
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F.von Nussbaum
et al.
(2015).
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.
PubMed id:
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Date:
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17-Apr-15
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Release date:
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19-Aug-15
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PROCHECK
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Headers
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References
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P08246
(ELNE_HUMAN) -
Neutrophil elastase from Homo sapiens
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Seq:
Struc:
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267 a.a.
218 a.a.
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Key: |
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PfamA domain |
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Secondary structure |
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CATH domain |
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Enzyme class:
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E.C.3.4.21.37
- leukocyte elastase.
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Reaction:
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Hydrolysis of proteins, including elastin. Preferential cleavage: Val-|-Xaa > Ala-|-Xaa.
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Chemmedchem
10:1163-1173
(2015)
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PubMed id:
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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.
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F.von Nussbaum,
V.M.Li,
S.Allerheiligen,
S.Anlauf,
L.Bärfacker,
M.Bechem,
M.Delbeck,
M.F.Fitzgerald,
M.Gerisch,
H.Gielen-Haertwig,
H.Haning,
D.Karthaus,
D.Lang,
K.Lustig,
D.Meibom,
J.Mittendorf,
U.Rosentreter,
M.Schäfer,
S.Schäfer,
J.Schamberger,
L.A.Telan,
A.Tersteegen.
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ABSTRACT
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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.
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Links
