Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket

Raphaël Frédérick, Caroline Charlier, Séverine Robert, Johan Wouters, Bernard Masereel, Lionel Pochet

Research output: Contribution to journalArticlepeer-review


The synthesis of novel coumarins bearing on the lateral side chain in the 3-position an amine or a guanidine group is described. In vitro evaluation highlighted 14d which possesses a meta aniline side chain as a very potent THR inhibitor. Surprisingly, the introduction of a guanidine moiety always led to a decrease in THR inhibiting properties. We, thus, used docking experiments to rationalize the SAR in the series. This study showed the crucial role of a conserved water molecule in the specificity pocket of THR during docking simulation in order to explain the inactivity of guanidine derivatives. © 2006 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)2017-2021
Number of pages5
JournalBioorganic and medicinal chemistry letters
Issue number7
Publication statusPublished - 1 Apr 2006


  • Coumarins
  • Docking
  • Mechanism-based inhibitor
  • Serine protease
  • Thrombin

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