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

Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs

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 originale	Anglais
Pages (de - à)	2017-2021
Nombre de pages	5
journal	Bioorganic and medicinal chemistry letters
Volume	16
Numéro de publication	7
Les DOIs	https://doi.org/10.1016/j.bmcl.2005.12.070
Etat de la publication	Publié - 1 avr. 2006

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10.1016/j.bmcl.2005.12.070

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Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors
Bouckaert, C., Serra, S., Rondelet, G., Dolusic, E., Wouters, J., Dogne, J-M., Frédérick, R. & Pochet, L., 3 mars 2016, Dans: European Journal of Medicinal Chemistry. p. 181-194 14 p., 110.
Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs
STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH
Bouckaert, C., Vancraeynest, C., Dolušić, E., Frédérick, R. & Pochet, L., 30 nov. 2012, p. Book of Abstracts, MedChem 2012, Château de Colonster, Liège - November 30, 2012, P01. 1 p.
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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.",

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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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 et al.
Dans: Bioorganic and medicinal chemistry letters, Vol 16, Numéro 7, 01.04.2006, p. 2017-2021.

Résultats de recherche: Contribution à un journal/une revue › Article › Revue par des pairs

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

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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.

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KW - Docking

KW - Mechanism-based inhibitor

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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

Résumé

Accès au document

Autres fichiers et liens

Empreinte digitale

Résultat de recherche

Synthesis, evaluation and structure-activity relationship of new 3-carboxamide coumarins as FXIIa inhibitors

STUDY OF COUMARINS WITH IMPROVED SOLUBILITY TO INHIBIT FXIIa, AN EMERGING TARGET IN THROMBOSIS RESEARCH

Équipement

Physico-chimie et caractérisation (PC2)

Spectrométrie de masse (MASUN)

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