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

Frédérick, Raphaël;Charlier, Caroline;Robert, S.;Wouters, Johan;Pochet, Lionel;et.al.
(2006) Bioorganic & Medicinal Chemistry Letters : the tetrahedron journal for research at the interface of chemistry and biology — Vol. 16, n° 7, p. 2017-2021 (2006)

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Authors
  • Frédérick, Raphaëlorcid-logoUCLouvain
    Author
  • Charlier, CarolineUnamur
    Author
  • Robert, S.orcid-logoUnamur
    Author
  • Wouters, JohanUnamur
    Author
  • Pochet, LionelUnamur
    Author
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Abstract
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.
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Frédérick, R., Charlier, C., Robert, S., Wouters, J., Masereel, B., & Pochet, L. (2006). Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket. Bioorganic & Medicinal Chemistry Letters : the tetrahedron journal for research at the interface of chemistry and biology, 16(7), 2017-2021. https://doi.org/10.1016/j.bmcl.2005.12.070 (Original work published 2006)