D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A(2) (IIa) with antiinflammatory activity

Hansford, Karl A., Reid, Robert C., Clark, Chris I., Tyndall, Joel D. A., Whitehouse, Michael W., Guthrie, Tom, McGeary, Ross P., Schafer, Karl, Martin, Jennifer L. and Fairlie, David P. (2003) D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A(2) (IIa) with antiinflammatory activity. Chembiochem, 4 2-3: 181-185. doi:10.1002/cbic.200390029


Author Hansford, Karl A.
Reid, Robert C.
Clark, Chris I.
Tyndall, Joel D. A.
Whitehouse, Michael W.
Guthrie, Tom
McGeary, Ross P.
Schafer, Karl
Martin, Jennifer L.
Fairlie, David P.
Title D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A(2) (IIa) with antiinflammatory activity
Formatted title
D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity
Journal name Chembiochem   Check publisher's open access policy
ISSN 1439-4227
Publication date 2003-01-01
Year available 2003
Sub-type Article (original research)
DOI 10.1002/cbic.200390029
Open Access Status Not yet assessed
Volume 4
Issue 2-3
Start page 181
End page 185
Total pages 5
Place of publication Weinheim, Germany
Publisher Wiley-VCH Verlag
Language eng
Subject C1
780103 Chemical sciences
0304 Medicinal and Biomolecular Chemistry
Abstract Few reported inhibitors of secretory phospholipase A(2) enzymes inhibit the IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivastised to give a series of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-Angstrom crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca2+ ion through carboxylate and amide oxygen atoms, H bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group-His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.
Keyword Biochemistry & Molecular Biology
Chemistry, Medicinal
Enzymes
Inflammation
Inhibitors
Medicinal Chemistry
Structure-activity Relationships
Face Aromatic Interactions
Molecular Torsion Balance
X-ray Structure
Crystal-structure
Recognition
Expression
Discovery
Selection
Mechanism
Proteins
Q-Index Code C1
Institutional Status UQ

 
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Created: Wed, 15 Aug 2007, 12:42:41 EST