Discovery of novel anti-prion compounds using in silico and in vitro approaches

TitleDiscovery of novel anti-prion compounds using in silico and in vitro approaches
Publication TypeJournal Article
Year of Publication2015
AuthorsHyeon JW, Choi J, Kim SY, Govindaraj RG, Jam Hwang K, Lee YS, An SSA, Lee MK, Joung JY, No KT, Lee J
JournalSci Rep
Volume5
Pagination14944
Date Published2015 Oct 09
ISSN2045-2322
KeywordsAnimals, Cell Line, Tumor, Computer Simulation, Drug Discovery, Humans, Ligands, Molecular Docking Simulation, Prion Diseases, Protein Binding, Protein Structure, Tertiary, PrPC Proteins, PrPSc Proteins, Surface Plasmon Resonance, Xenobiotics
Abstract

Prion diseases are associated with the conformational conversion of the physiological form of cellular prion protein (PrP(C)) to the pathogenic form, PrP(Sc). Compounds that inhibit this process by blocking conversion to the PrP(Sc) could provide useful anti-prion therapies. However, no suitable drugs have been identified to date. To identify novel anti-prion compounds, we developed a combined structure- and ligand-based virtual screening system in silico. Virtual screening of a 700,000-compound database, followed by cluster analysis, identified 37 compounds with strong interactions with essential hotspot PrP residues identified in a previous study of PrP(C) interaction with a known anti-prion compound (GN8). These compounds were tested in vitro using a multimer detection system, cell-based assays, and surface plasmon resonance. Some compounds effectively reduced PrP(Sc) levels and one of these compounds also showed a high binding affinity for PrP(C). These results provide a promising starting point for the development of anti-prion compounds.

DOI10.1038/srep14944
Alternate JournalScientific Reports

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