Estudos funcionais de potenciais inibidores da enzima chiquimato quinase de Mycobacterium tuberculosis

• Ano de defesa: 2022
• Autor(a) principal: Freitas, Talita Freitas de
• Orientador(a): Basso, Luiz Augusto
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Pontifícia Universidade Católica do Rio Grande do Sul
• Programa de Pós-Graduação: Programa de Pós-Graduação em Medicina e Ciências da Saúde
• Departamento: Escola de Medicina
• País: Brasil
• Palavras-chave em Português: Tuberculose; Via do Chiquimato; Chiquimato Quinase; Docagem Molecular; AutoDock Vina; PyRx; pkCSM; Concentração Inibitória Mínima
• Palavras-chave em Inglês: Tuberculosis; Shikimate Pathway; Shikimate Kinase; Docking Molecular; AutoDock Vina; PyRx; pkCSM; Minimal Inhibitory Concentration
• Área do conhecimento CNPq: CIENCIAS DA SAUDE::MEDICINA
• Link de acesso: https://tede2.pucrs.br/tede2/handle/tede/10473

In 2017, the Tuberculosis (TB) was considered one of the top 10 causes of death worldwide. The drug therapy currently used in the TB treatment allows the patient to quickly relieve symptoms, which encourages them, in some cases, to prematurely discontinue treatment. The TB resistant has reached increasingly alarming levels around the world, making it essential that new therapeutic strategies are developed to circumvent the resistance mechanisms of mycobacteria. Given this scenario, it is necessary to identify and propose new molecular targets that are, ideally, essential, vulnerable, and selective. The shikimic acid pathway has received notable attention due to the identification of one of the enzymes, 5-enolpyruvylshikimate-3-phosphate (ESPS) synthase, as a molecular target of the herbicide glyphosate (N-(phosphonomethyl)glycine). The absence in animals and essentiality in plants, fungi and bacteria suggest that structure-based chemotherapeutic development of anti-TB agents which are less toxic to the host is warranted using the shikimic acid pathway enzymes as targets. This project main goal is to identify potential inhibitors of compounds belonging to a library of Laboratório de Química do Centro de Pesquisas em Biologia Molecular e Funcional (CPBMF) using the shikimate kinase (SK) enzyme of M. tuberculosis (MtSK) as therapeutic target for the development of new drugs to treat TB. Two tridimensional structures of the SK (PDB ID: 2IYS e 2IYQ), available in the protein databank (PDB), were used in a molecular docking, based on a pre-established protocol (redocking) by the AutoDock Vina software. The prediction of toxicity and hepatotoxicity of the compounds were performed through the pkCSM web server, which filtered 298, which does not have hepatotoxic and mutagenic character. From the interaction between the structures of the components and the visual interaction of the characteristics of the components that most interacted with the enzyme site. The Maximum assay allowed by the solubility of the solution 17 were performed in in vitro assays. Those from compounds 1a, 1b, 3a, 3d and 5c had inhibitory potential to the enzyme and mycobacteria, thus demonstrating compounds a from a library front of promissory notes, not designed for an MtSK enzyme.