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The compound (3-{5-[(2,5-dimethoxyphenyl)amino]-1,3,4-thiadiazolidin-2-yl}-5,8-methoxy-2H-chromen-2-one) inhibits the prion protein conversion from PrPC to PrPSc with lower IC50 in ScN2a cells

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dc.contributor.author Pagadala, Nataraj S.
dc.contributor.author Bjorndahl, Trent C.
dc.contributor.author Joyce, Michael
dc.contributor.author Wishart, David S.
dc.contributor.author Syed, Khajamohiddin
dc.contributor.author Landi, Abdolamir
dc.date.accessioned 2018-12-05T06:31:07Z
dc.date.available 2018-12-05T06:31:07Z
dc.date.issued 2017
dc.identifier.uri http://hdl.handle.net/11462/1813
dc.description Published Article en_US
dc.description.abstract Prion diseases are fatal neurodegenerative disorders of the central nervous system characterized by the accumulation of a protease resistant form (PrPSc) of the cellular prion protein (PrPC) in the brain. Two types of cellular prion (PrPC) compounds have been identified that appear to affect prion conversion are known as Effective Binders (EBs) and Accelerators (ACCs). Effective binders shift the balance in favour of PrPC, whereas Accelerators favour the formation of PrPSc. Molecular docking indicates EBs and ACCs both bind to pocket-D of the SHaPrPC molecule. However, EBs and ACCs may have opposing effects on the stability of the salt bridge between Arg156 and Glu196/Glu200. Computational docking data indicate that the hydrophobic benzamide group of the EB, GFP23 and the 1-(3,3-dimethylcyclohexylidene)piperidinium group of the ACC, GFP22 play an important role in inhibition and conversion from SHaPrPC to SHaPrPSc, respectively. Experimentally, NMR confirmed the amide chemical shift perturbations observed upon the binding of GFP23 to pocket-D of SHaPrPC. Consistent with its role as an ACC, titration of GFP22 resulted in widespread chemical shift changes and signal intensity loss due to protein unfolding. Virtual screening of a ligand database using the molecular scaffold developed from the set of EBs identified six of our compounds (previously studied using fluorescence quenching) as being among the top 100 best binders. Among them, compounds 5 and 6 were found to be particularly potent in decreasing the accumulation SHaPrPSc in ScN2a cells with an IC50 of 35 mM and 20 mM. en_US
dc.format.extent 3 631 885 bytes, 1 file
dc.format.mimetype Application/PDF
dc.language.iso en_US en_US
dc.publisher Elsevier Ltd: Bioorganic & Medicinal Chemistry en_US
dc.relation.ispartofseries Volume 25;Issue 20
dc.subject Prion en_US
dc.subject Docking en_US
dc.subject HQSAR en_US
dc.subject CoMFA en_US
dc.subject NMR en_US
dc.subject ScN2a cells en_US
dc.title The compound (3-{5-[(2,5-dimethoxyphenyl)amino]-1,3,4-thiadiazolidin-2-yl}-5,8-methoxy-2H-chromen-2-one) inhibits the prion protein conversion from PrPC to PrPSc with lower IC50 in ScN2a cells en_US
dc.type Article en_US

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