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Bioorg Med Chem. 2017 Oct 15;25(20):5875-5888. doi: 10.1016/j.bmc.2017.09.024. Epub 2017 Sep 19.

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.

Author information

1
Department of Medical Microbiology and Immunology, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1, Canada. Electronic address: nattu251@gmail.com.
2
Department of Biological Sciences, and Computing Science, University of Alberta, Edmonton, Alberta T6G 2E8, Canada.
3
Department of Medical Microbiology and Immunology, 6-020 Katz Group Centre, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
4
Unit for Drug Discovery Research, Department of Health Sciences, Faculty of Health and Environmental Sciences, Central University of Technology, Bloemfontein 9300, Free State, South Africa.
5
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.

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 ∼35µM and 20µM.

KEYWORDS:

CoMFA; Docking; HQSAR; NMR; Prion; ScN2a cells

PMID:
28951092
DOI:
10.1016/j.bmc.2017.09.024
[Indexed for MEDLINE]

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