Partial filling affinity capillary electrophoresis as a useful tool for fragment-based drug discovery: A proof of concept on thrombin

Eléna Farcas, C. Bouckaert, Anne Catherine Servais, Julien Hanson, L. Pochet, Marianne Fillet

Résultats de recherche: Contribution à un journal/une revueArticleRevue par des pairs

Résumé

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 μM 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.
langue originaleAnglais
Pages (de - à)211-222
Nombre de pages12
journalAnalytica chimica acta
Volume984
Date de mise en ligne précoce2017
Les DOIs
Etat de la publicationPublié - 1 sept. 2017

Empreinte digitale Examiner les sujets de recherche de « Partial filling affinity capillary electrophoresis as a useful tool for fragment-based drug discovery: A proof of concept on thrombin ». Ensemble, ils forment une empreinte digitale unique.

Contient cette citation