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

doi:10.1016/j.bmcl.2005.12.070

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 journal › Article

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. © 2006 Elsevier Ltd. All rights reserved.

Original language	English
Pages (from-to)	2017-2021
Number of pages	5
Journal	Bioorganic and medicinal chemistry letters
Volume	16
Issue number	7
DOIs	https://doi.org/10.1016/j.bmcl.2005.12.070
Publication status	Published - 1 Apr 2006

Keywords

Coumarins
Docking
Mechanism-based inhibitor
Serine protease
Thrombin

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10.1016/j.bmcl.2005.12.070

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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 and medicinal chemistry letters, 16(7), 2017-2021. https://doi.org/10.1016/j.bmcl.2005.12.070

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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, Séverine ; Wouters, Johan ; Masereel, Bernard ; Pochet, Lionel.

In: Bioorganic and medicinal chemistry letters, Vol. 16, No. 7, 01.04.2006, p. 2017-2021.

Research output: Contribution to journal › Article

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AU - Masereel, Bernard

AU - Pochet, Lionel

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