INTEGRATIVE MODEL OF RHODANINE DERIVATIVES AS TAU AGGREGATION INHIBITORS IN ALZHEIMER'S DISEASE
Résumé
Tau aggregation is responsible for the formation of neurofibrillary tangles which is one hallmark of Alzheimer's disease. Short hexapeptides of Tau (PHF6) are known to be responsible for the formation of aggregates. Rhodanine-based compounds are known as Tau anti-aggregation inhibitors. However, their precise mode of action on Tau is still undefined, e.g. the binding site(s), binding mode(s), or stoichiometry remain undefined. To date, there is no structural data on Tau complex with any Rhodanine derivatives, and there is no rationale for their activity or toxicity. Three computational modelling approaches have been used to propose an integrative model for the mode of action of Rhodanine derivatives. First, QSAR studies were used to identify and quantify the molecular properties relevant to their activity and toxicity. The more active and less active compounds were then used in docking simulation to identify the possible binding modes and the contacts specific to the more active compounds. Finally, molecular dynamics simulations were performed to validate the 3D models of interaction between Tau (PHF6) and the more active Rhodanine compound and determine the more probable stoichiometry. Possible pathways for their insertion into the aggregated PHF6 peptides are also identified suggesting how they may act as Tau anti-aggregation inhibitors.
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