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Probing the Anti-Sickling Power of Distinct Drugs in Sickle Cell Disease
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Resumo(s)
Sickle cell disease (SCD) is a genetic blood disorder that affects millions of people worldwide. The disease is characterized by anemia, pain crises, and a higher risk of stroke and heart attack. SCD is caused
by a mutation in the gene that encodes the β subunit of hemoglobin, originating an abnormal form of
hemoglobin known as HbS, where a Glu-β6 is replaced by a Val-β6 in the β-globins. The aggregation of
this protein is responsible for the disease and is therefore a worthwhile target for drug activity. Despite
being investigated for years, an easily applicable, reliable, and cheap treatment remains elusive. Therefore, it is essential to search for novel inhibitors for treatment of this illness. The focus of this thesis is
identification and investigation of the potential therapeutic effect of several molecules identified through
in silico methodologies to probe their specificity and anti-sickling potential via blockage of the pocket
involved in the formation of fibers or other areas of the protein surface.
For this purpose, molecular docking was initially used to screen a commercially available compound
database as well as a number of drugs previously identified through in vitro studies. The screening focused on the hydrophobic pocket where the mutated Val residue is lodged in the fibers. Three high scoring
and three low-scoring compounds from molecular docking were selected for further studies. Docking did
not reveal a significant difference between these two sets, with both compound types featuring reported
in vitro anti-sickling activity, exhibiting long pocket residence times and similar binding energies. All
were found to bind with good affinity to the valine 6 residue, as observed in contact analysis through
MD simulations. Future studies should consider other screening methodologies as well as additional
simulations and in vitro experiments to assess the aggregation inhibition potential of these and related
molecules.
Descrição
Tese de mestrado, Bioquímica e Biomedicina, 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Anemia Falciforme Sangue Hemoglobina Docking Molecular Dinâmica Molecular Teses de mestrado - 2024