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Identification by in silico and in vitro screenings of small organic molecules acting as reversible inhibitors of kallikreins.

Abstract
Netherton syndrome is caused by loss-of-function mutations in SPINK5 encoding the Kazal-type inhibitor LEKTI-1 leading to dysregulation of proteolytic cascades involving several kallikreins. We used both structure-based and ligand-based virtual screening computations to identify commercially available non-covalent inhibitors of human kallikrein 5 (hK5), a serine protease (trypsin-like) that plays a central role in the initiation of the molecular cascades leading to the Netherton syndrome phenotype. The efficacy and mechanism of inhibition of the identified new families of organic compounds were analyzed not only for hK5 but also on other proteases implicated in the cascades (hK7, hK14 and matriptase). These inhibitors are nontoxic on healthy human keratinocytes and are structurally different from traditional serine protease inhibitors validating their potential utility as initial hits to control proteolytic disorders observed in dermatological pathologies such as Netherton syndrome.
AuthorsXiao Tan, Claudia Bertonati, Lixian Qin, Laetitia Furio, Chahrazade El Amri, Alain Hovnanian, Michèle Reboud-Ravaux, Bruno O Villoutreix
JournalEuropean journal of medicinal chemistry (Eur J Med Chem) Vol. 70 Pg. 661-8 ( 2013) ISSN: 1768-3254 [Electronic] France
PMID24211642 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Masson SAS. All rights reserved.
Chemical References
  • Serine Proteinase Inhibitors
  • Small Molecule Libraries
  • Kallikreins
Topics
  • Dose-Response Relationship, Drug
  • High-Throughput Screening Assays
  • Humans
  • Kallikreins (antagonists & inhibitors, metabolism)
  • Models, Molecular
  • Molecular Structure
  • Serine Proteinase Inhibitors (chemistry, pharmacology)
  • Small Molecule Libraries (chemistry, pharmacology)
  • Structure-Activity Relationship

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