Lipid bilayer position and orientation of novel carprofens, modulators of γ-secretase in Alzheimer's disease
Jazyk angličtina Země Nizozemsko Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
30409518
DOI
10.1016/j.bbamem.2018.09.003
PII: S0005-2736(18)30267-0
Knihovny.cz E-zdroje
- Klíčová slova
- Alzheimer's disease, Drug discovery, Molecular dynamics, Neutron diffraction, Nuclear magnetic resonance, γ-Secretase,
- MeSH
- Alzheimerova nemoc metabolismus MeSH
- karbazoly metabolismus farmakologie MeSH
- lidé MeSH
- lipidové dvojvrstvy * MeSH
- magnetická rezonanční spektroskopie metody MeSH
- sekretasy účinky léků metabolismus MeSH
- simulace molekulární dynamiky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- carprofen MeSH Prohlížeč
- karbazoly MeSH
- lipidové dvojvrstvy * MeSH
- sekretasy MeSH
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.
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