Computational search for inhibitors of amyloid beta aggregation in Alzheimer's disease
Gruppi di ricerca 28- biomedica
Tipo tesi COMPUTATIONAL
Descrizione Alzheimer's Disease (AD) is associated with a progressive degeneration of brain structure and function, but what triggers the cascade? Zinc binds Aβ with high specificity and saturability, contributing to the promotion of amyloid-beta (Aβ) plaque formation within the brain. Hallmarks of AD including tau phosphorylation, Aβ aggregation, and neurofibrillary tangle (NFT) formation, are dependent upon zinc. Our previous work showed that zinc-rich Aβ plaque formation could deplete concentrations of intracellular zinc, cause microtubule destabilization, increase oxidative stress, and accelerate neurodegeneration4. Could zinc dyshomeostasis induce sporadic forms of AD?
The proposed study will address the following question: What is the role of zinc in AD pathogenesis? Using an in silico, virtual screening tool, we will isolate candidate molecules optimized to bind with or modulate binding to the zinc region on beat amyloid protein and assess their impact on protein-protein binding. Virtual screening saves time and resources, isolating drugs that are most likely to interact with zinc-based mechanisms in the cell.
While the literature supports a zinc-based mechanism for AD pathogenesis, the link may ultimately be correlative, representing a risk. To guard against this potential pitfall, the hybrid platform that we will build can easily be re-calibrated to assess the role of other hypothesized mechanisms of AD.
The main outcomes of this project are: 1) An empirical assessment of the validity of the zinc dyshomeostasis hypothesis, identifying mechanistic interactions between amyloid beat bound with zinc and without as well as in the presence of the putative inhibitors.
Conoscenze richieste molecular docking, bioinformatics, familiarity with Molecular Operating Environment software
Scadenza validita proposta 07/07/2023 PROPONI LA TUA CANDIDATURA