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

Résultats de recherche: Contribution à un journal/une revueArticle

Résumé

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.

langue originaleAnglais
Pages (de - à)2017-2021
Nombre de pages5
journalBioorganic and medicinal chemistry letters
Volume16
Numéro de publication7
Les DOIs
étatPublié - 1 avr. 2006

Empreinte digitale

Coumarins
Guanidine
Thrombin
Molecules
Water
Bearings (structural)
Amines
Derivatives
Experiments

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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. {\circledC} 2006 Elsevier Ltd. All rights reserved.",
keywords = "Coumarins, Docking, Mechanism-based inhibitor, Serine protease, Thrombin",
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",
year = "2006",
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doi = "10.1016/j.bmcl.2005.12.070",
language = "English",
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journal = "Bioorganic and medicinal chemistry letters",
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publisher = "Elsevier Limited",
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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 -