Fiche publication
Date publication
octobre 2014
Journal
Journal of medicinal chemistry
Auteurs
Membres identifiés du Cancéropôle Est :
Dr GONCALVES Victor
Tous les auteurs :
Hutton JA, Goncalves V, Brannigan JA, Paape D, Wright MH, Waugh TM, Roberts SM, Bell AS, Wilkinson AJ, Smith DF, Leatherbarrow RJ, Tate EW
Lien Pubmed
Résumé
Inhibitors of Leishmania N-myristoyltransferase (NMT), a potential target for the treatment of leishmaniasis, obtained from a high-throughput screen, were resynthesized to validate activity. Crystal structures bound to Leishmania major NMT were obtained, and the active diastereoisomer of one of the inhibitors was identified. On the basis of structural insights, enzyme inhibition was increased 40-fold through hybridization of two distinct binding modes, resulting in novel, highly potent Leishmania donovani NMT inhibitors with good selectivity over the human enzyme.
Mots clés
Acyltransferases, antagonists & inhibitors, Chemistry Techniques, Synthetic, Crystallography, X-Ray, Enzyme Inhibitors, chemical synthesis, High-Throughput Screening Assays, methods, Leishmania donovani, enzymology, Leishmania major, enzymology, Models, Molecular, Structure-Activity Relationship
Référence
J. Med. Chem.. 2014 Oct;57(20):8664-70
