Galamba, Nuno Jorge Rosa Lopes, 1974-Victor, Bruno Lourenço da SilvaNeto, Vasco Miguel dos Santos2024-03-082024-12-2920242023http://hdl.handle.net/10451/63293Tese de mestrado, Bioquímica e Biomedicina, 2023, Universidade de Lisboa, Faculdade de CiênciasSickle 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.engAnemia FalciformeSangueHemoglobinaDocking MolecularDinâmica MolecularTeses de mestrado - 2024master thesis203683412