PDBsum entry 1eat

Hydrolase (serine protease)

PDB id: 1eat

Contents

Protein chain

240 a.a. *

Ligands

SO4 ×2

TFI

Metals

_NA

Waters ×126

* Residue conservation analysis

PDB id:

1eat

Name:

Hydrolase (serine protease)

Title:

Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and x-ray crystallography of a series of orally active 5- amino-pyrimidin-6-one-containing trifluoromethylketones

Structure:

Porcine pancreatic elastase. Chain: a. Engineered: yes

Source:

Sus scrofa. Pig. Organism_taxid: 9823

Resolution:

2.00Å R-factor: 0.167

Authors:

C.Ceccarelli

Key ref:

C.A.Veale et al. (1995). Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl ketones. J Med Chem, 38, 98. PubMed id: 7837246

Date:

22-Nov-94 Release date: 07-Feb-95

Protein chain

P00772  (CELA1_PIG) -  Chymotrypsin-like elastase family member 1 from Sus scrofa

Seq: 266 a.a.

Struc: 240 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.3.4.21.36 - pancreatic elastase.
• Reaction: Hydrolysis of proteins, including elastin. Preferential cleavage: Ala-|-Xaa.

J Med Chem 38:98 (1995)

PubMed id: 7837246

Nonpeptidic inhibitors of human leukocyte elastase. 5. Design, synthesis, and X-ray crystallography of a series of orally active 5-aminopyrimidin-6-one-containing trifluoromethyl ketones.

C.A.Veale, P.R.Bernstein, C.Bryant, C.Ceccarelli, J.R.Damewood, R.Earley, S.W.Feeney, B.Gomes, B.J.Kosmider, G.B.Steelman.

ABSTRACT

The effects of changes in substitution in a series of 5-amino-2-pyrimidin-6-ones on both in vitro activity and oral activity in an acute hemorrhagic assay have been explored. These compounds contained either a trifluoromethyl ketone or a boronic acid moiety to bind covalently to the Ser-195 hydroxyl of human leukocyte elastase (HLE). Boronic acid-containing inhibitors were found to be more potent than the corresponding trifluoromethyl ketones in vitro but were less active upon oral administration. Compound 13b was found to offer the best combination of oral potency, duration of action, and enzyme selectivity and, as such, was selected for further biological testing. X-ray crystallography of a cocrystallized complex of compound 19m and porcine pancreatic elastase demonstrated that the inhibitor is bound to the enzyme in a manner similar to that found previously for a closely related series of pyridone-containing inhibitors of HLE.