Prion diseases are serious, not curable neurodegenerative disorders caused by the accumulation of the misfolded protein PrPSc that represents the pathological variant of the normally folded cellular protein PrPC. Molecules that bind the cellular isoform PrPC preventing its misfolding, could arrest the progression of pathological conditions related to the abnormal PrP protein. In this context, by combining 3D-QSAR model, derived from pharmacophore-based alignment, with molecular docking procedures and physico-chemical properties prediction we have developed a virtual screening protocol to find novel chemicals able to prevent PrPC misfolding. We identified different hits characterized by low toxicity and able to inhibit PrPSc accumulation in vitro in prion-infected neuroblastoma cell lines (ScN2a). In this assay, the pyrroloquinoxaline hydrazone 96 showed the higest potency with an IC50 value of 1.6 μM. Pyrroloquinoxaline 96 was demonstrated also to bind PrPSc aggregates in infected ScN2a cells with a fluorescence pattern comparable to that found for Thioflavin-T. In consideration of its satisfactory physico-chemical properties, including predicted blood brain barrier permeability, 96 could represent an interesting prototypic hit for the development of diagnostic and therapeutic probes for prion diseases.
Keywords: 3D-QSAR; Anti-Prion agents; Pharmacophore modeling; Prion; Theranostic tools.
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