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Biological evaluation and docking studies of natural isocoumarins as inhibitors for human kallikrein 5 and 7.

Abstract
Human kallikrein 5 and 7 (KLK5 and KLK7) are trypsin-like and chymotrypsin-like serine proteases, respectively, and promising targets for the treatment of skin desquamation, inflammation and cancer. In an effort to develop new inhibitors for these enzymes, we carried out enzymatic inhibition assays and docking studies with three isocoumarin compounds. Some promising inhibitors were uncovered, with vioxanthin and 8,8'-paepalantine being the most potent competitive inhibitors of KLK5 (K(i)=22.9 μM) and KLK7 (K(i)=12.2 μM), respectively. Our docking studies showed a good correlation with the experimental results, and revealed a distinct binding mode for the inhibitors at the binding sites of KLK5 and KLK7. In addition, the docking results suggested that the formation of hydrogen bonds at the oxyanion hole is essential for a good inhibitor.
AuthorsThiago S P Teixeira, Renato F Freitas, Odonírio Abrahão Jr, Karina F Devienne, Lucas R de Souza, Sachico I Blaber, Michael Blaber, Marcia Y Kondo, Maria A Juliano, Luiz Juliano, Luciano Puzer
JournalBioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 21 Issue 20 Pg. 6112-5 (Oct 15 2011) ISSN: 1464-3405 [Electronic] England
PMID21903387 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2011 Elsevier Ltd. All rights reserved.
Chemical References
  • Isocoumarins
  • KLK5 protein, human
  • KLK7 protein, human
  • Kallikreins
  • Serine Endopeptidases
Topics
  • Humans
  • Isocoumarins (chemistry, pharmacology)
  • Kallikreins (antagonists & inhibitors, metabolism)
  • Models, Molecular
  • Protein Binding
  • Serine Endopeptidases (chemistry, pharmacology)

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