Navegando por Palavras-chave "Drug Design"
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- ItemAcesso aberto (Open Access)Arilalquilpiperazinas como agentes multialvo moduladores de receptores histaminérgicos, dopaminérgicos e da acetilcolinesterase(Universidade Federal de São Paulo (UNIFESP), 2021) Aranha, Cecilia Maria Simoes De Queiroz [UNIFESP]; Fernandes, João Paulo dos Santos [UNIFESP]; Universidade Federal de São PauloSeveral neurological disorders can be associated with cognitive decline, and the mechanisms responsible for controlling these disorders are complex and diverse. The role of cholinergic, histaminergic and dopaminergic neurotransmission has considerable relevance for the development of these difunctions, and the heterogeneous nature indicates that multi-target strategies, considering targets associated to these systems, may be more appropriate in the treatment of these disfunctions. In this scenario, this work presents a series of 24 arylalkylpiperazines, with different aromatic nuclei (naphthyl, benzofuranyl and quinolinyl), linkers (ethylene and propylene) and substituents in the piperazine terminal nitrogen (methyl, phenyl and pyridyl), synthesized from classic organic reactions, which led to yields varying from 21 to 97%. Out of these, 12 compounds were evaluated at histamine H3 (H3R) and H4 (H4R) and dopamine D2 (D2R) and D3 (D3R) receptors through binding assays, while 21 compounds were evaluated for acetylcholinesterase (AChE) inhibition using a modified Ellman’s method. Seven compounds showed good affinity for H3R, with compound LINS05014 showing the best affinity (1,1 µM), and most showed good selectivity over H4R. Four compounds showed good affinity for D3R, with compound LINS05006 showing the best affinity (0,7 µM), and also showed good selectivity over D2R. The compounds showed low affinity for AChE, with compound LINS05030 showing the best affinity (72,7 µM). As for multitargeting approach, two compounds showed to be promising in the three selected targets (LINS05006 = Ki: H3R = 2.8 µM; D3R = 0.7 µM; IC50: AChE = 107.1 µM; LINS05020 = Ki: H3R = 1.7 µM; D3R = 1.4 µM; IC50: AChE = 114.7µM) and can be used as a prototype, together with overall results, to improve the development of better multitargeting ligands.
- ItemAcesso aberto (Open Access)Desenho racional de inibidores da protease principal do SARS-CoV-2(Universidade Federal de São Paulo, 2023-12-12) Montilla, Rafael Augusto Girao [UNIFESP]; Wurtele, Martin Alejandro [UNIFESP]; http://lattes.cnpq.br/0625673643875019; http://lattes.cnpq.br/9507082785734180Este estudo utiliza o software Gnina para realizar o docking molecular para investigar as interações moleculares de novos compostos sintetizados através da reação de Ugi. O foco está no desenvolvimento de inibidores não covalentes direcionados à Protease Principal (Mpro) do SARS-CoV-2. Os resultados de docking são empregados para calcular energias livres de ligação, e esses valores são correlacionados com a concentração inibitória (IC50). Para estabelecer esta correlação, simulações de dockings virtual são conduzidas para compostos conhecidos da literatura com valores medidos de IC50 contra SARS-CoV-2 Mpro. Todos os compostos avaliados, pertencentes à mesma classe de inibidores, são caracterizados como pseudopeptídeos não covalentes. A análise dos dockins revela insights sobre os aspectos estruturais da inibição do Mpro, enfatizando os bolsões S1, S2, S3 e S4 no sítio ativo. O estudo identifica dois leads potenciais; ambos os compostos exibem um modo de ligação invertido em comparação com os peptídeos clivados por Mpro. A abordagem de bioinformática estrutural aqui empregada fornece informações valiosas para o projeto de novos inibidores não covalentes contra SARS-CoV-2 Mpro. É necessária validação adicional através de testes in vitro para confirmar o potencial inibitório dos compostos concebidos. Este estudo contribui para a nossa compreensão das interações moleculares envolvidas na inibição do SARS-CoV-2 Mpro e estabelece as bases para o desenvolvimento de terapêutica antiviral eficaz.
- ItemSomente MetadadadosPyrazinamide and pyrazinoic acid derivatives directed to mycobacterial enzymes against tuberculosis(Bentham science publ ltd, 2016) Correa, Michelle Fidelis [UNIFESP]; Fernandes, Joao Paulo dos Santos [UNIFESP]Tuberculosis (TB) is an infectious diseases responsible for thousands of deaths worldwide. Due to the use of antimycobacterial drugs, TB prevalence seemed to be controlled, but with the appearance of resistant tuberculosis cases, the concern about the disease had become significant again, as well as the need for new alternatives to TB treatment. Since pyrazinamide (PZA) is part of the first-line agents in TB treatment, several derivatives of this drug were described, besides pyrazinoic acid (POA) derivatives, the active form of PZA. POA has been used mainly to design prodrugs to be activated by mycobacterial esterases, while PZA derivatives should be activated specifically by the nicotinamidase/ pyrazinamidase (PZAse), or other PZAse-independent pathways. The intention of this paper is to discuss the state of art of PZA and POA derivatives and their activity against Mycobacterium tuberculosis and other mycobacteria, besides the therapeutic potential. Focus was given in prodrugs and derivatives directed to mycobacterial enzymes involved in its activation or mechanism of action.