Computational studies of small molecules-inhibitors of Aβ peptide’s aggregation in Alzheimer's disease

Postgraduate Thesis uoadl:3248939 4 Read counter

Κατεύθυνση Βιοπληροφορική-Υπολογιστική Βιολογία
Library of the School of Science
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Bezantakou Dimitra
Supervisors info:
Βασιλική Α. Οικονομίδου, Αναπληρώτρια Καθηγήτρια, Τμήμα Βιολογίας, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Ιωάννης Π. Τρουγκάκος, Καθηγητής, Τμήμα Βιολογίας, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Νικόλαος Χ. Παπανδρέου, Δρ, Ε.ΔΙ.Π., Τμήμα Βιολογίας, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Original Title:
Υπολογιστικές μελέτες μικρών μορίων-αναστολέων της συσσωμάτωσης του πεπτιδίου Aβ στη νόσο του Alzheimer
Translated title:
Computational studies of small molecules-inhibitors of Aβ peptide’s aggregation in Alzheimer's disease
Amyloid beta (Aβ) peptide results from the proteolytic cleavage of the transmembrane amyloid precursor protein (APP). The structural changes and the subsequent aggregation of the peptide in the brain are a decisive event in the pathogenesis of Alzheimer's disease, which is by far the most common cause of dementia worldwide. The disease is clinically characterized by the presence of neurofibrillary tangles of tau proteins and amyloid plaques in brain, with the main component in the latter being the Aβ peptide. Contemporary data demonstrate the oligomer stage of Aβ peptide as the most toxic, possibly triggering the onset of events leading to neuronal death. Therefore, inhibition of the oligomerized Aβ peptide may play a critical role in drug development and natural products are valuable candidates. Many plants of the Greek flora are traditionally used for their therapeutic properties due to the abundance of secondary metabolites. These small organic molecules have served as a valuable source of bioactive compounds due to their unique chemical structures and often favorable pharmacokinetic properties. Many of them show anti-inflammatory, antioxidant and anti-amyloidogenic activity in several in vitro and in vivo experiments and are therefore considered a promising strategy for the prevention and treatment of neurodegenerative diseases. Subject matter of this thesis is the study and evaluation of potential inhibitors of the oligomerized Aβ peptide, derived from plant species of the genus Cistus that grow in Greece, using computational methods. Rigid receptor-Flexible ligand Molecular Docking and Molecular Dynamics simulations were used, in order to investigate the most active ligands that alter the structural integrity of oligomerized Aβ peptide and are able to inhibit its aggregation in Alzheimer's disease. Furthermore, the computational evaluation of the pharmacokinetic properties of the candidate inhibitors was performed. Nine of the 109 ligands were deemed sufficiently successful by the preliminary Molecular Docking study and were subjected to molecular dynamics simulations. All ligands retained their topological affinity with the Aβ peptide pentamer, forming stable complexes, while almost all compounds altered the structural conformation of the peptide, which is responsible for its pathological activity. A decrease in the number of amino acid residues of the oligomer that take part in β-strands was observed, and at the same time, helical structures, which characterize the normal monomer, appeared, in some cases for long periods of time. Particularly, promising inhibitors are Benzyl benzoate, 3-(3-Methylphenyl) propiophenone and Carvacrol since, in combination with quite positive results regarding the Molecular Dynamics simulations, they also show favorable pharmacokinetic properties, with the in silico evaluation predicting that they can penetrate the blood-brain barrier. Therefore, these three compounds could act as potential inhibitors of toxic oligomerized amyloid beta peptide, thereby targeting a fundamental disease mechanism.
Main subject category:
Bioinformatics, Computational Biology, Molecular Docking, Molecular Dynamics simulation, Alzheimer disease, amyloid beta, aggregation, natural products, Cistus
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File access is restricted until 2025-11-24.