Hampering the early aggregation of PrP-E200K protein by charge-based inhibitors: a computational study

Mariangela Agamennone,Roberto Paciotti,Alessandro Marrone,Loriano Storchi

doi:10.1007/s10822-021-00393-7

Mariangela Agamennone, Roberto Paciotti + Show 2 more

Open Access

https://doi.org/10.1007/s10822-021-00393-7

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Abstract

A multilayered computational workflow was designed to identify a druggable binding site on the surface of the E200K pathogenic mutant of the human prion protein, and to investigate the effect of the binding of small molecules in the inhibition of the early aggregation of this protein. At this purpose, we developed an efficient computational tool to scan the molecular interaction properties of a whole MD trajectory, thus leading to the characterization of plausible binding regions on the surface of PrP-E200K. These structural data were then employed to drive structure-based virtual screening and fragment-based approaches to the seeking of small molecular binders of the PrP-E200K. Six promising compounds were identified, and their binding stabilities were assessed by MD simulations. Therefore, analyses of the molecular electrostatic potential similarity between the bound complexes and unbound protein evidenced their potential activity as charged-based inhibitors of the PrP-E200K early aggregation.

Highlights

Since its proposal by Prusiner [1, 2], the prion’s concept have entered in the body of knowledge of several fields of Chemistry and Biology, and several neurodegenerative diseases are currently categorized to be caused by prions or prion-like proteins [3]
The identification of suitable binding sites to host small molecules on the prion protein (PrP)-E200K structure was preliminarily carried out on the experimentally determined 30 NMR structures of this protein (PDB ID 1FO7) [59] using SiteMap as described in the “Method” section. Such an analysis allowed the identification of several possible binding regions on the protein surface; none of them presented a good profile of binding features with respect to the parameters suggested from the SiteMap manual (SiteScore > 0.80, exposure < 0.49, enclosure > 0.78, balance ≥ 1.6)
The analysis on the experimental structures of PrP-E200K corroborated the presence of a potential binding pocket located between H2 and S1, this site was affected by high solvent exposure, and reduced accessibility of hydrophobic residues (Table S1)

Summary

Introduction

Since its proposal by Prusiner [1, 2], the prion’s concept have entered in the body of knowledge of several fields of Chemistry and Biology, and several neurodegenerative diseases are currently categorized to be caused by prions or prion-like proteins [3]. Several pathogenic mutants of PrP have been recognized to be causative of familial forms of prion diseases, all characterized by a sudden inset leading to rapid decline of neurological. The E200K mutation of PrP is recognized to be the cause of the most common familial form of the Creutzfeldt-Jakob disease (CJD) [10]. Both heterozygous and homozygous mutants have been investigated to elucidate the pathogenic role played by E200K, especially to discern among loss-offunction or attainment of new protein functions [14]

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Conclusion