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 & 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

Access to Document

10.1016/j.bmcl.2005.12.070

Cite this

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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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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.
In: Bioorganic & 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

SN - 0960-894X

VL - 16

SP - 2017

EP - 2021

JO - Bioorganic & Medicinal Chemistry Letters

JF - Bioorganic & Medicinal Chemistry Letters

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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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

Mass Spectrometry Service

Physical Chemistry and characterization(PC2)

Cite this

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Research output

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

Equipment

Mass Spectrometry Service

Physical Chemistry and characterization(PC2)

Cite this