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Variety of antiprion compounds discovered through an in silico screen based on cellular-form prion protein structure: Correlation between antiprion activity and binding affinity.

ABSTRACT: Transmissible spongiform encephalopathies are associated with the conformational conversion of the prion protein from the cellular form (PrP(C)) to the scrapie form. This process could be disrupted by stabilizing the PrP(C) conformation, using a specific ligand identified as a chemical chaperone. To discover such compounds, we employed an in silico screen that was based on the nuclear magnetic resonance structure of PrP(C). In combination, we performed ex vivo screening using the Fukuoka-1 strain-infected neuronal mouse cell line at a compound concentration of 10 microM and surface plasmon resonance. Initially, we selected 590 compounds according to the calculated docked energy and finally discovered 24 efficient antiprion compounds, whose chemical structures are quite diverse. Surface plasmon resonance studies showed that the binding affinities of compounds for PrP(C) roughly correlated with the compounds' antiprion activities, indicating that the identification of chemical chaperones that bind to the PrP(C) structure and stabilize it is one efficient strategy for antiprion drug discovery. However, some compounds possessed antiprion activities with low affinities for PrP(C), indicating a mechanism involving additional modulation factors. We classified the compounds roughly into five categories: (i) binding and effective, (ii) low binding and effective, (iii) binding and not effective, (iv) low binding and not effective, and (v) acceleration. In conclusion, we found a spectrum of compounds, many of which are able to modulate the pathogenic conversion reaction. The appropriate categorization of these diverse compounds would facilitate antiprion drug discovery and help to elucidate the pathogenic conversion mechanism.

SUBMITTER: Hosokawa-Muto J

PROVIDER: S-EPMC2630596 | biostudies-literature | 2009 Feb

REPOSITORIES: biostudies-literature

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Variety of antiprion compounds discovered through an in silico screen based on cellular-form prion protein structure: Correlation between antiprion activity and binding affinity.

Hosokawa-Muto Junji J Kamatari Yuji O YO Nakamura Hironori K HK Kuwata Kazuo K

Antimicrobial agents and chemotherapy 20081117 2

Transmissible spongiform encephalopathies are associated with the conformational conversion of the prion protein from the cellular form (PrP(C)) to the scrapie form. This process could be disrupted by stabilizing the PrP(C) conformation, using a specific ligand identified as a chemical chaperone. To discover such compounds, we employed an in silico screen that was based on the nuclear magnetic resonance structure of PrP(C). In combination, we performed ex vivo screening using the Fukuoka-1 strai ...[more]

PMID: 19015328

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Project description:The prion protein (PrP) is implicated in the Transmissible Spongiform Encephalopathies (TSEs), which comprise a group of fatal neurodegenerative diseases affecting humans and other mammals. Conversion of cellular PrP (PrP(C)) into the scrapie form (PrP(Sc)) is the hallmark of TSEs. Once formed, PrP(Sc) aggregates and catalyzes PrP(C) misfolding into new PrP(Sc) molecules. Although many compounds have been shown to inhibit the conversion process, so far there is no effective therapy for TSEs. Besides, most of the previously evaluated compounds failed in vivo due to poor pharmacokinetic profiles. In this work we propose a combined in vitro/in silico approach to screen for active anti-prion compounds presenting acceptable drugability and pharmacokinetic parameters. A diverse panel of aromatic compounds was screened in neuroblastoma cells persistently infected with PrP(Sc) (ScN2a) for their ability to inhibit PK-resistant PrP (PrP(Res)) accumulation. From ?200 compounds, 47 were effective in decreasing the accumulation of PrP(Res) in ScN2a cells. Pharmacokinetic and physicochemical properties were predicted in silico, allowing us to obtain estimates of relative blood brain barrier permeation and mutagenicity. MTT reduction assays showed that most of the active compounds were non cytotoxic. Compounds that cleared PrP(Res) from ScN2a cells, were non-toxic in the MTT assay, and presented a good pharmacokinetic profile were investigated for their ability to inhibit aggregation of an amyloidogenic PrP peptide fragment (PrP(109-149)). Molecular docking results provided structural models and binding affinities for the interaction between PrP and the most promising compounds. In summary, using this combined in vitro/in silico approach we have identified new small organic anti-scrapie compounds that decrease the accumulation of PrP(Res) in ScN2a cells, inhibit the aggregation of a PrP peptide, and possess pharmacokinetic characteristics that support their drugability. These compounds are attractive candidates for prion disease therapy.

Dataset Information

Variety of antiprion compounds discovered through an in silico screen based on cellular-form prion protein structure: Correlation between antiprion activity and binding affinity.

Publications

Variety of antiprion compounds discovered through an in silico screen based on cellular-form prion protein structure: Correlation between antiprion activity and binding affinity.

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