title: In silico strategies on prion pathogenic conversion and inhibition from PrPC-PrPSc.
abstract: To date, various therapeutic strategies identified numerous anti-prion compounds and antibodies that stabilize PrPC, block the conversion of PrPC-PrPScand increased effect on PrPScclearance. However, no suitable drug has been identified clinically so far due to the poor oral absorption, low blood-brain-barrier [BBB] penetration, and high toxicity. Although some of the drugs were proven to be effective in prion-infected cell culture and whole animal models, none of them increased the rate of survival compared to placebo. Areas covered: In this review, the authors highlight the importance of in silico approaches like molecular docking, virtual screening, pharmacophore analysis, molecular dynamics, QSAR, CoMFA and CoMSIA applied to detect molecular mechanisms of prion inhibition and conversion from PrPC-PrPSc. Expert opinion: Several in silico approaches combined with experimental studies have provided many structural and functional clues on the stability and physiological activity of prion mutants. Further, various studies of in silico and in vivo approaches were also shown to identify several new small organic anti-scrapie compounds to decrease the accumulation of PrPresin cell culture, inhibit the aggregation of a PrPCpeptide, and possess pharmacokinetic characteristics that confirm the drug-likeness of these compounds.
authors.affiliation: a Department of Medical Microbiology and Immunology, 6-020 Katz Group Centre , University of Alberta , Edmonton , Canada.
authors.forename: Nataraj S
authors.initials: NS
authors.lastname: Pagadala
authors.affiliation: b Unit for Drug Discovery Research, Department of Health Sciences, Faculty of Health and Environmental Sciences , Central University of Technology , Bloemfontein , South Africa.
authors.forename: Khajamohiddin
authors.initials: K
authors.lastname: Syed
authors.affiliation: a Department of Medical Microbiology and Immunology, 6-020 Katz Group Centre , University of Alberta , Edmonton , Canada.
authors.forename: Rakesh
authors.initials: R
authors.lastname: Bhat
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D003198:Computer Simulation; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D062105:Molecular Docking Simulation; D018621:PrPC Proteins / Q000187:drug effects / Q000378:metabolism; D018620:PrPSc Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D017096:Prion Diseases / Q000188:drug therapy*; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: D018621:PrPC Proteins; D018620:PrPSc Proteins
keywords: CoMFA (Comparative Molecular Field Analysis); CoMSIA (Comparative Molecular Similarity Indices); Prion; QSAR (Quantitative Structure Activity Relationship); docking; molecular dynamics (MD)