Article (Scientific journals)
Partial filling affinity capillary electrophoresis as a useful tool for fragment-based drug discovery: A proof of concept on thrombin.
Farcas, Elena; Bouckaert, C.; Servais, Anne-Catherine et al.
2017In Analytica Chimica Acta, 984, p. 211-222
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Keywords :
Affinity capillary electrophoresis; Fragment-based drug discovery; Inhibitor; Thrombin
Abstract :
[en] With the emergence of more challenging targets, a relatively new approach, fragment-based drug discovery (FBDD), proved its efficacy and gained increasing importance in the pharmaceutical industry. FBDD identifies low molecular-weight (MW) ligands (fragments) that bind to biologically important macromolecules, then a structure-guided fragment growing or merging approach is performed, contributing to the quality of the lead. However, to select the appropriate fragment to be evolved, sensitive analytical screening methods must be used to measure the affinity in the muM or even mM range. In this particular context, we developed a robust and selective partial filling affinity CE (ACE) method for the direct binding screening of a small fragment library in order to identify new thrombin inhibitors. To demonstrate the accuracy of our assay, the complex dissociation constants of three known thrombin inhibitors, namely benzamidine, p-aminobenzamidine and nafamostat were determined and found to be in good concordance with the previously reported values. Finally, the screening of a small library was performed and demonstrated the high discriminatory power of our method towards weak binders compared to classical spectrophotometric activity assay, proving the interest of our method in the context of FBDD.
Research center :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Farcas, Elena ;  Université de Liège - ULiège > Département de pharmacie > Analyse des médicaments
Bouckaert, C.
Servais, Anne-Catherine  ;  Université de Liège > Département de pharmacie > Analyse des médicaments
Hanson, Julien  ;  Université de Liège > Département de pharmacie > Chimie pharmaceutique
Pochet, L.
Fillet, Marianne  ;  Université de Liège > Département de pharmacie > Analyse des médicaments
Language :
English
Title :
Partial filling affinity capillary electrophoresis as a useful tool for fragment-based drug discovery: A proof of concept on thrombin.
Publication date :
2017
Journal title :
Analytica Chimica Acta
ISSN :
0003-2670
eISSN :
1873-4324
Publisher :
Elsevier, Netherlands
Volume :
984
Pages :
211-222
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2017 Elsevier B.V. All rights reserved.
Available on ORBi :
since 05 September 2017

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