Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados
Caffeic acid is a natural compound belonging to the phenylpropanoid class that has different pharmacological properties. Thus, in order to enhance the effects of caffeic acid, we used the molecular hybridization technique of caffeic acid with monoterpenic alcohols, reported in the literature as prom...
| Autor principal: | Strada, Mayara Fernanda |
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| Formato: | Trabalho de Conclusão de Curso (Graduação) |
| Idioma: | Português |
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Universidade Tecnológica Federal do Paraná
2022
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riut-1-289462022-07-01T06:06:06Z Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados In silico studies aiming pharmacological application of idealized monoterpenic cafeates Strada, Mayara Fernanda Romero, Adriano Lopes Romero, Rafaelle Bonzanini Peron, Ana Paula Romero, Adriano Lopes Mamas - Câncer Farmacologia Deidrogenases Agentes antineoplásicos Compostos bioativos Breast - Cancer Pharmacology Dehydrogenases Antineoplastic agents Bioactive compounds CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA Caffeic acid is a natural compound belonging to the phenylpropanoid class that has different pharmacological properties. Thus, in order to enhance the effects of caffeic acid, we used the molecular hybridization technique of caffeic acid with monoterpenic alcohols, reported in the literature as promising therapeutic agents. Thus, in this study, in silico, in order to reduce costs and time, the pharmacokinetic properties and pharmacological potential of caffeic acid (1), ten monoterpenic alcohols (2-11) and ten idealized monoterpenic cafeates (12-21), resulting from the hybridization of caffeic acid with monoterpenic alcohols: (+)-linalool (2), menthol (3), myrtenol (4), peryl alcohol (5), verbenol (6), cyclohexanol (7), carveol (8), citronellol (9), geraniol (10) and (-)-linalool (11). The molecular and pharmacological properties were evaluated using cheminformatics tools. From the analysis of data obtained from Molinspiration, it can be observed that there was no violation of Lipinski's rule of five, thus, it is likely that the compounds evaluated present good oral bioavailability. Furthermore, Molinspiration indicated pharmacological potential for the compounds, and the results obtained with the Swiss Target Prediction tool indicated that most idealized hybrids significantly pointed to the inhibition of the enzyme 17-beta-dehydrogenase 2. With molecular docking it was observed that all compounds evaluated were anchored in the channel that is the active site of the enzyme. The enzyme has two access slits to the active site and most compounds were closer to the larger slit, which is further away from the active site. Therefore, such interactions may not result in enzymatic inhibition, moreover, it was found that compounds 14 and 19 anchored in the active site of the enzyme, interacting with the amino acid residue Tyr 155, this could be confirmed by the dendrogram generated in the software. The ADMET properties of the compounds were also evaluated, which showed negative results for the P-glycoprotein inhibition parameter and substrate and most of the compounds evaluated, except for compound 10, do not inhibit the cytochrome CYP 450 isoforms. Regarding mutagenicity and carcinogenicity, it was observed that the evaluated compounds had negative results for the mutagenicity model, and only compound 8 had a positive result for this model, thus, there is little or no toxicity for the compounds. Thus, the compounds showed ADMET parameters suitable for drug candidates. According to the results obtained, myrtenyl and citronyl caffeates (compounds 14 and 19) presented as a potential target for inhibition the enzyme 17-beta-dehydrogenase 2 and by molecular anchoring, the compounds anchored in the active site of the enzyme and interacted with an effective energy with the amino acid residue Tyr 155 present in its active site. Furthermore, these cafeates showed pharmacokinetic and pharmacological properties suitable for drug candidates. These results indicate the potential to invest in in vitro or in vivo tests to continue research and development of new drugs. Thus, these two cafeates have potential activity to inhibit the enzyme 17-beta-dehydrogenase 2, and act in the treatment of breast cancer. O ácido cafeico é um composto natural pertencente à classe dos fenilpropanóides que possui diferentes propriedades farmacológicas. Assim, visando potencializar os efeitos do ácido cafeico, utilizou-se a técnica de hibridação molecular do ácido cafeico com álcoois monoterpênicos, reportados na literatura como promissores agentes terapêuticos. Dessa forma, no presente trabalho avaliou-se in silico, a fim de reduzir custos e tempo, as propriedades farmacocinéticas e o potencial farmacológico do ácido cafeico (1), de dez álcoois monoterpênicos (2-11) e dos dez cafeatos monoterpênicos idealizados (12-21), resultantes da hibridação do ácido cafeico com os álcoois monoterpênicos:(+)-linalol (2), mentol (3), mirtenol (4), álcool perílico (5), verbenol (6), cicloexanol (7), carveol (8), citronelol (9), geraniol (10) e (-)-linalol (11). As propriedades moleculares e farmacológicas foram avaliadas por meio de ferramentas de quimioinformática. A partir da análise dos dados obtidos no Molinspiration observa-se que não houve nenhuma violação à regra dos cinco de Lipinski, desse modo, é provável que os compostos avaliados apresentem boa biodisponibilidade oral. Além disso, o Molinspiration indicou potencial farmacológico para os compostos, e os resultados obtidos na ferramenta Swiss Target Prediction indicaram que a maioria dos híbridos idealizados apontaram significativamente para a inibição da enzima 17-beta-desidrogenase 2. Com o docking molecular observou-se que todos os compostos avaliados se encontravam ancorados no canal que está localizado o sítio ativo da enzima. A enzima possui duas fendas de acesso ao sítio ativo e a maioria dos compostos ficaram mais próximos à fenda maior, que está mais distante do sítio ativo. Logo tais interações podem não resultar em inibição enzimática, ademais, verificou-se que os compostos 14 e 19 ancoraram-se no sítio ativo da enzima, interagindo com o resíduo de aminoácido Tyr 155, isso pôde ser confirmado pelo dendrograma gerado no software. Avaliou-se também as propriedades ADMET dos compostos, que apresentaram resultados negativos para o parâmetro de inibição e substrato da glicoproteína-P e a maioria dos compostos avaliados, exceto o composto 10, não inibem as isoformas do citocromo CYP 450. Em relação à mutagenicidade e carcinogecidade, observou-se que os compostos avaliados apresentaram resultados negativos para o modelo de mutagenicidade, e apenas o composto 8 apresentou resultado positivo para esse modelo, desse modo, constata-se uma baixa ou nula toxicidade para os compostos. Assim, os compostos apresentaram parâmetros ADMET condizentes para candidatos à fármacos. De acordo com os resultados obtidos, os cafeatos de mirtenila e citronila (compostos 14 e 19) apresentaram como potencial alvo de inibição a enzima 17-beta-desidrogenase 2 e mediante a ancoragem molecular, os compostos ancoraramse no sítio ativo da enzima e interagiram com uma energia efetiva com o resíduo de aminoácido Tyr 155 presente no sítio ativo da mesma. Ademais, esses cafeatos apresentaram propriedades farmacocinéticas e farmacológicas condizentes para candidatos à fármacos. Tais resultados indicam a potencialidade de investir em testes in vitro ou in vivo para continuação da pesquisa e desenvolvimento de novos fármacos. Assim, esses dois cafeatos possuem potencial atividade para inibir a enzima 17-beta-desidrogenase 2, e atuar no tratamento do câncer de mama. 2022-06-30T11:53:45Z 2022-06-30T11:53:45Z 2021-12-02 bachelorThesis STRADA, Mayara Fernanda. Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados. 2021. Trabalho de Conclusão de Curso (Licenciatura em Química) - Universidade Tecnológica Federal do Paraná, Campo Mourão, 2021. http://repositorio.utfpr.edu.br/jspui/handle/1/28946 por openAccess Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Universidade Tecnológica Federal do Paraná Campo Mourao Brasil Departamento Acadêmico de Química Licenciatura em Química UTFPR |
| institution |
Universidade Tecnológica Federal do Paraná |
| collection |
RIUT |
| language |
Português |
| topic |
Mamas - Câncer Farmacologia Deidrogenases Agentes antineoplásicos Compostos bioativos Breast - Cancer Pharmacology Dehydrogenases Antineoplastic agents Bioactive compounds CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA |
| spellingShingle |
Mamas - Câncer Farmacologia Deidrogenases Agentes antineoplásicos Compostos bioativos Breast - Cancer Pharmacology Dehydrogenases Antineoplastic agents Bioactive compounds CNPQ::CIENCIAS EXATAS E DA TERRA::QUIMICA Strada, Mayara Fernanda Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados |
| description |
Caffeic acid is a natural compound belonging to the phenylpropanoid class that has different pharmacological properties. Thus, in order to enhance the effects of caffeic acid, we used the molecular hybridization technique of caffeic acid with monoterpenic alcohols, reported in the literature as promising therapeutic agents. Thus, in this study, in silico, in order to reduce costs and time, the pharmacokinetic properties and pharmacological potential of caffeic acid (1), ten monoterpenic alcohols (2-11) and ten idealized monoterpenic cafeates (12-21), resulting from the hybridization of caffeic acid with monoterpenic alcohols: (+)-linalool (2), menthol (3), myrtenol (4), peryl alcohol (5), verbenol (6), cyclohexanol (7), carveol (8), citronellol (9), geraniol (10) and (-)-linalool (11). The molecular and pharmacological properties were evaluated using cheminformatics tools. From the analysis of data obtained from Molinspiration, it can be observed that there was no violation of Lipinski's rule of five, thus, it is likely that the compounds evaluated present good oral bioavailability. Furthermore, Molinspiration indicated pharmacological potential for the compounds, and the results obtained with the Swiss Target Prediction tool indicated that most idealized hybrids significantly pointed to the inhibition of the enzyme 17-beta-dehydrogenase 2. With molecular docking it was observed that all compounds evaluated were anchored in the channel that is the active site of the enzyme. The enzyme has two access slits to the active site and most compounds were closer to the larger slit, which is further away from the active site. Therefore, such interactions may not result in enzymatic inhibition, moreover, it was found that compounds 14 and 19 anchored in the active site of the enzyme, interacting with the amino acid residue Tyr 155, this could be confirmed by the dendrogram generated in the software. The ADMET properties of the compounds were also evaluated, which showed negative results for the P-glycoprotein inhibition parameter and substrate and most of the compounds evaluated, except for compound 10, do not inhibit the cytochrome CYP 450 isoforms. Regarding mutagenicity and carcinogenicity, it was observed that the evaluated compounds had negative results for the mutagenicity model, and only compound 8 had a positive result for this model, thus, there is little or no toxicity for the compounds. Thus, the compounds showed ADMET parameters suitable for drug candidates. According to the results obtained, myrtenyl and citronyl caffeates (compounds 14 and 19) presented as a potential target for inhibition the enzyme 17-beta-dehydrogenase 2 and by molecular anchoring, the compounds anchored in the active site of the enzyme and interacted with an effective energy with the amino acid residue Tyr 155 present in its active site. Furthermore, these cafeates showed pharmacokinetic and pharmacological properties suitable for drug candidates. These results indicate the potential to invest in in vitro or in vivo tests to continue research and development of new drugs. Thus, these two cafeates have potential activity to inhibit the enzyme 17-beta-dehydrogenase 2, and act in the treatment of breast cancer. |
| format |
Trabalho de Conclusão de Curso (Graduação) |
| author |
Strada, Mayara Fernanda |
| author_sort |
Strada, Mayara Fernanda |
| title |
Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados |
| title_short |
Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados |
| title_full |
Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados |
| title_fullStr |
Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados |
| title_full_unstemmed |
Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados |
| title_sort |
estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados |
| publisher |
Universidade Tecnológica Federal do Paraná |
| publishDate |
2022 |
| citation |
STRADA, Mayara Fernanda. Estudos in silico visando aplicação farmacológica de cafeatos monoterpênicos idealizados. 2021. Trabalho de Conclusão de Curso (Licenciatura em Química) - Universidade Tecnológica Federal do Paraná, Campo Mourão, 2021. |
| url |
http://repositorio.utfpr.edu.br/jspui/handle/1/28946 |
| _version_ |
1805319307931942912 |
| score |
10,814766 |