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

Namur Research Institute for Life Sciences

Research output: Contribution to journal › Article › peer-review

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

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. {\textcopyright} 2006 Elsevier Ltd. All rights reserved.",

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author = "Rapha{\"e}l Fr{\'e}d{\'e}rick and Caroline Charlier and S{\'e}verine Robert and Johan Wouters and Bernard Masereel and Lionel Pochet",

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doi = "10.1016/j.bmcl.2005.12.070",

language = "English",

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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 › peer-review

TY - JOUR

T1 - Investigation of mechanism-based thrombin inhibitors: Implications of a highly conserved water molecule for the binding of coumarins within the S pocket

AU - Frédérick, Raphaël

AU - Charlier, Caroline

AU - Robert, Séverine

AU - Wouters, Johan

AU - Masereel, Bernard

AU - Pochet, Lionel

PY - 2006/4/1

Y1 - 2006/4/1

N2 - 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.

AB - 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.

KW - Coumarins

KW - Docking

KW - Mechanism-based inhibitor

KW - Serine protease

KW - Thrombin

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U2 - 10.1016/j.bmcl.2005.12.070

DO - 10.1016/j.bmcl.2005.12.070

M3 - Article

C2 - 16413781

VL - 16

SP - 2017

EP - 2021

JO - Bioorganic and medicinal chemistry letters

JF - Bioorganic and medicinal chemistry letters

SN - 0960-894X

IS - 7

ER -

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

Abstract

Keywords

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