Lipid bilayer position and orientation of novel carprofens, modulators of γ-secretase in Alzheimer's disease.
Fiche publication
Date publication
novembre 2018
Journal
Biochimica et biophysica acta. Biomembranes
Auteurs
Membres identifiés du Cancéropôle Est :
Pr BECHINGER Burkhard
Tous les auteurs :
Salnikov E, Drung B, Fabre G, Itkin A, Otyepka M, Dencher NA, Schmidt B, Hauß T, Trouillas P, Bechinger B
Lien Pubmed
Résumé
γ-Secretase is an integral membrane protein complex and is involved in the cleavage of the amyloid precursor protein APP to produce amyloid-β peptides. Amyloid-β peptides are considered causative agents for Alzheimer's disease and drugs targeted at γ-secretase are investigated as therapeutic treatments. We synthesized new carprofen derivatives, which showed γ-secretase modulating activity and determined their precise position, orientation, and dynamics in lipid membranes by combining neutron diffraction, solid-state NMR spectroscopy, and molecular dynamics simulations. Our data indicate that the carprofen derivatives are inserted into the membrane interface, where the exact position and orientation depends on the lipid phase. This knowledge will help to understand the docking of carprofen derivatives to γ-secretase and in the design of new potent drugs. The approach presented here promises to serve as a general guideline how drug/target interactions in membranes can be analyzed in a comprehensive manner.
Mots clés
Alzheimer's disease, Drug discovery, Molecular dynamics, Neutron diffraction, Nuclear magnetic resonance, γ-Secretase
Référence
Biochim Biophys Acta Biomembr. 2018 Nov;1860(11):2224-2233