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 PrP to PrP with lower IC in ScN2a cells.

Bioorg Med Chem

Department of Medical Microbiology and Immunology, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1, Canada; Department of Immunology, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

Published: October 2017

Prion diseases are fatal neurodegenerative disorders of the central nervous system characterized by the accumulation of a protease resistant form (PrP) of the cellular prion protein (PrP) in the brain. Two types of cellular prion (PrP) 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 PrP, whereas Accelerators favour the formation of PrP. Molecular docking indicates EBs and ACCs both bind to pocket-D of the SHaPrP molecule. However, EBs and ACCs may have opposing effects on the stability of the salt bridge between Arg and Glu/Glu. 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 SHaPrP to SHaPrP, respectively. Experimentally, NMR confirmed the amide chemical shift perturbations observed upon the binding of GFP23 to pocket-D of SHaPrP. 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 SHaPrP in ScN2a cells with an IC of ∼35µM and 20µM.

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http://dx.doi.org/10.1016/j.bmc.2017.09.024DOI Listing

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