Discovery of Potent Inhibitors of Schistosoma mansoni NAD(+) Catabolizing Enzyme.
Fiche publication
Date publication
avril 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Dr WAGNER Alain
Tous les auteurs :
Jacques SA, Kuhn I, Koniev O, Schuber F, Lund FE, Wagner A, Muller-Steffner H, Kellenberger E
Lien Pubmed
Résumé
The blood fluke Schistosoma mansoni is the causative agent of the intestinal form of schistosomiasis (or bilharzia). Emergence of Schistosoma mansoni with reduced sensitivity to praziquantel, the drug currently used to treat this neglected disease, has underlined the need for development of new strategies to control schistosomiasis. Our ability to screen drug libraries for antischistosomal compounds has been hampered by the lack of validated S. mansoni targets. In the present work, we describe a virtual screening approach to identify inhibitors of S. mansoni NAD(+) catabolizing enzyme (SmNACE), a receptor enzyme suspected to be involved in immune evasion by the parasite at the adult stage. Docking of commercial libraries into a homology model of the enzyme has led to the discovery of two in vitro micromolar inhibitors. Further structure-activity relationship studies have allowed a 3-log gain in potency, accompanied by a largely enhanced selectivity for the parasitic enzyme over the human homologue CD38.
Référence
J Med Chem. 2015 Apr 23;58(8):3582-92