Prion diseases are a group of rare
neurodegenerative diseases caused by the structural conversion of cellular
prion into
Scrapie prion resulting aggregated fibrils.
Therapy of
prion diseases has been developed for several decades, especially
drug designs based on the structure of
prion monomers. Unfortunately, none of the designed anti-
prion drugs function well clinically. To fight against
prion fibrils, a
drug design based on the precise structure of mammalian
prion fibrils is highly required. Fortunately, based on the advantage of newly advanced cryo-electron microscopy (cryo-EM) in the deconvolution of large complexes, three
prion fibril structures were resolved in the last 2 years. Based on the cryo-EM solved
prion fibril structures, we are able to find some molecules fighting against
prion fibrils.
Quercetin, one
flavonoid molecule in the
polyphenol group, has been found to disaggregate the
prion fibrils in vitro. In this study, we performed the molecular docking and molecular dynamics simulation on
quercetin-like molecules possessing pharmacological properties to evaluate the anti-
prion ability of tested molecules. As a result, four
quercetin-like molecules interact with
prion fibril and decrease the β-strand content by converting some β-strands into loop and helical structures to disintegrate the existing fibril structure. The results of this study are significant in the treatment of
prion diseases, and the approaches used in this study are applicable to other
amyloid diseases.