Estudos de farmacologia in silico de ésteres fenólicos idealizados visando à obtenção de inibidores de tirosina quinase
According to the World Health Organization (WHO), cancer is the second leading cause of death in the world and constitutes a public health problem in several countries, including Brazil, clearly highlighting the need for an intensified global focus on prevention and in the treatment of cancer. Curre...
| Autor principal: | Gabriel, Bruno Pereira |
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| Formato: | Trabalho de Conclusão de Curso (Graduação) |
| Idioma: | Português |
| Publicado em: |
Universidade Tecnológica Federal do Paraná
2021
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| Assuntos: | |
| Acesso em linha: |
http://repositorio.utfpr.edu.br/jspui/handle/1/25608 |
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| Resumo: |
According to the World Health Organization (WHO), cancer is the second leading cause of death in the world and constitutes a public health problem in several countries, including Brazil, clearly highlighting the need for an intensified global focus on prevention and in the treatment of cancer. Currently, cancer chemotherapy plays an important role in cancer therapy, however, the antineoplastic drugs available today still cause serious side effects and adverse reactions, highlighting the need for more effective and safe research and planning of innovative drugs. Thus, in order to contribute to advances in cancer chemotherapy, the present study aimed to evaluate in silico the pharmacokinetic properties and bioactivities of idealized phenolic caffeates. For this purpose, 10 phenolic caffeates were conceived that can be obtained by esterifying with phenolic compounds (phenol, o-salicylaldehyde, guaiacol, p-cresol, vanillin, p-salicylaldehyde, eugenol, paeonol, carvacrol and thymol), evaluated the pharmacokinetic and toxicological profile of each substance using bioinformatics and chemoinformatics tools and a molecular docking study was carried out against the enzyme tyrosine kinase (PDB: 1AD5). According to the results obtained, some phenolic caffeates demonstrated potential inhibition for the enzyme tyrosine kinase analyzed in the molecular anchorage study, and some caffeates interacted at the kinase domain binding site through interaction with the amino acid residues Leu-393, Val-281 Glu-339 and Met-341, competing with the substrate for the active site, thus, can inhibit the enzymatic activity of this bioreceptor. It should be noted that in the context of cancer chemotherapy, the inhibition of tyrosine kinases is an important strategy to suppress the advance of cancer cells. In addition, the different substances evaluated in this study showed adequate molecular and pharmacokinetic properties for possible drug candidates, so that the toxicity values are within the accepted range (Category III), also including the toxicity of the metabolites, and showed negative results for the carcinogenicity and mutagenesis model (AMES test). Regarding absorption, none of the compounds violated Lipinski's “Rule of 5”, so they must have good oral bioavailability; and also demonstrated positive values for permeability in Caco-2 cells and are not substrates or inhibitors of P-Glycoprotein, therefore, they are absorbed in the intestine and are likely to have good absorption if administered orally. Regarding the inhibition of different cytochrome P450 isoforms, only a few molecules showed positive values for inhibition of certain isoforms. Therefore, the compounds showed good ADMET properties and a favorable interaction with the enzyme tyrosine kinase in the molecular anchorage study. In addition, the results show the need for more computational studies to confirm the results, in particular new studies of molecular anchoring by more dynamic models for more accurate results. |
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