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

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 purpos...

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Bibliographic Details
Published in:Journal of computer-aided molecular design 2021-06, Vol.35 (6), p.751-770
Main Authors: Agamennone, Mariangela, Storchi, Loriano, Marrone, Alessandro, Paciotti, Roberto
Format: Article
Language:English
Subjects:
Agglomeration
Animal Anatomy
Binders
Binding Sites
Chemistry
Chemistry and Materials Science
Computer Applications in Chemistry
Histology
Humans
Hydrophobic and Hydrophilic Interactions
Inhibitors
Ligands
Molecular Dynamics Simulation
Molecular interactions
Morphology
Mutant Proteins - chemistry
Physical Chemistry
Prions - antagonists & inhibitors
Prions - chemistry
Prions - genetics
Protein Binding
Protein Conformation
Proteins
Software
Static Electricity
Structure-Activity Relationship
Workflow
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Summary: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.
ISSN:0920-654X
1573-4951
DOI:10.1007/s10822-021-00393-7