Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A
Autor(a) principal: | |
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Data de Publicação: | 2021 |
Tipo de documento: | Dissertação |
Idioma: | por |
Título da fonte: | Biblioteca Digital de Teses e Dissertações da UFPB |
Texto Completo: | https://repositorio.ufpb.br/jspui/handle/123456789/22624 |
Resumo: | RNA viruses have been a major problem for the entire world, given their easy replication, mutation and transmission. Specifically, influenza A is an RNA virus responsible for a high number of deaths, whether acting alone or aggravating several existing pathological conditions. Given the situation that this virus brings to the population and taking into account the few drugs used for the treatment of influenza A, it is extremely important to search for drug candidates that do not have as many side effects and that are effective for it, in alternative to current treatments, stressing the importance of candidates that act on multiple targets (multitarget), seeking through these, more effective and promising drugs, since, among the main advantages, it has the ability to block more than one target, obtaining better effectiveness and strength profiles. Thus, medicinal chemistry, through the use of computational tools, has been essential in the drug planning process, as it allows the optimization of time and operating costs. Associated with this, the growing number of cases resulting from endemic diseases, such as influenza A, has encouraged funding agencies to invest in research for the development of molecules that could be used in the treatment of such diseases. Thus, the aim of the present work was to propose natural molecules with potential anti-influenza A activity, predicted by a consensus analysis of three biological activity prediction models and analyzed by a hybrid virtual screening. In view of this, the database of 986 natural molecules were screened, first, through consensus analysis from 3 predictive models of biological activity, which resulted in only 36 molecules predicted to be active for influenza A and with excellent percentage of reliability, resulting from the construction of the 3 predictive models. Subsequently, these molecules were subjected to analyzes of the profile of absorption and oral bioavailability, risks of toxicity and metabolism against CYP 450. Molecular docking, against the 4 main proteins involved in the replication cycle of influenza A, namely: M2 channel, hemagglutinin, neuraminidase and RNA polymerase. With such results, in general all molecules showed excellent interactions against the 4 main proteins of influenza A, with emphasis on the HER03 molecule, which proved to be a potential drug candidate acting on multiple targets, considering the results that presented scores of interaction energies higher than for all control drugs and for all 4 proteins involved in the influenza A replication cycle. In view of these results, it was demonstrated that of the 986 natural molecules, 7 had potential to be drug candidates against influenza A, highlighting the HER03 molecule, which showed promising and potential results to be a candidate for an anti-influenza A drug acting on multiple targets. |
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Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza AInfluenza AMultitargetQuímica medicinaDocagem molecularMedicinal chemistryMolecular dockingCNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIARNA viruses have been a major problem for the entire world, given their easy replication, mutation and transmission. Specifically, influenza A is an RNA virus responsible for a high number of deaths, whether acting alone or aggravating several existing pathological conditions. Given the situation that this virus brings to the population and taking into account the few drugs used for the treatment of influenza A, it is extremely important to search for drug candidates that do not have as many side effects and that are effective for it, in alternative to current treatments, stressing the importance of candidates that act on multiple targets (multitarget), seeking through these, more effective and promising drugs, since, among the main advantages, it has the ability to block more than one target, obtaining better effectiveness and strength profiles. Thus, medicinal chemistry, through the use of computational tools, has been essential in the drug planning process, as it allows the optimization of time and operating costs. Associated with this, the growing number of cases resulting from endemic diseases, such as influenza A, has encouraged funding agencies to invest in research for the development of molecules that could be used in the treatment of such diseases. Thus, the aim of the present work was to propose natural molecules with potential anti-influenza A activity, predicted by a consensus analysis of three biological activity prediction models and analyzed by a hybrid virtual screening. In view of this, the database of 986 natural molecules were screened, first, through consensus analysis from 3 predictive models of biological activity, which resulted in only 36 molecules predicted to be active for influenza A and with excellent percentage of reliability, resulting from the construction of the 3 predictive models. Subsequently, these molecules were subjected to analyzes of the profile of absorption and oral bioavailability, risks of toxicity and metabolism against CYP 450. Molecular docking, against the 4 main proteins involved in the replication cycle of influenza A, namely: M2 channel, hemagglutinin, neuraminidase and RNA polymerase. With such results, in general all molecules showed excellent interactions against the 4 main proteins of influenza A, with emphasis on the HER03 molecule, which proved to be a potential drug candidate acting on multiple targets, considering the results that presented scores of interaction energies higher than for all control drugs and for all 4 proteins involved in the influenza A replication cycle. In view of these results, it was demonstrated that of the 986 natural molecules, 7 had potential to be drug candidates against influenza A, highlighting the HER03 molecule, which showed promising and potential results to be a candidate for an anti-influenza A drug acting on multiple targets.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqOs vírus de RNA tem sido uma grande problemática para todo o mundo, tendo em vista sua fácil replicação, mutação e transmissão. Especificamente, o influenza A é um vírus de rna responsável por um alto número de óbitos, seja atuando isoladamente ou agravando diversos quadros patológicosjá existentes. Diante do quadro que tal vírustrás para a população e levando em consideração os poucos fármacos existentes para o tratamento do influenza A, é de suma importância a busca por candidatos a fármacos que não apresentem tanto efeitos colaterais e que sejam eficazes para o mesmo, em alternativa aos atuais tratamentos, salientando a importância de candidatos que atuem em múltiplos alvos (multitarget), buscando através destes, fármacos mais eficazes e promissores, uma vez que, dentre as principais vantagens, tem a capacidade de bloquear mais de um alvo, obtendo melhor eficácia e perfis de resistência. Deste modo, a química medicinal, através da utilização de ferramentas computacionais, tem sido essencial no processo de planejamento de fármacos, uma vez que possibilita a otimização do tempo e de custos operacionais. Associado a isto, o crescente número de casos decorrentes de doenças endêmicas, como o influenza A, vem estimulando os órgãos de fomento a investir em pesquisas para o desenvolvimento de moléculas que possam serem utilizadas no tratamento de tais. Com isso, o objetivo do presente trabalho foi propor moléculas naturais com potencial atividade anti-influenza A, predita por uma análise de consenso de três modelos de predição de atividade biológica e analisadas por uma triagem virtual hibrida. Frente a isto, o banco de dados de 986 moléculas naturais, foram triadas, através primeiramente, da análise por consenso oriundas de 3 modelos de predição de atividade biológica, o que resultou em apenas 36 moléculas preditas como ativas para o influenza A e com ótimo percentual de confiabilidade, resultante da construção dos 3 modelos preditivos. Posteriormente, tais moléculas foram submetidas a análises do perfil de absorção e biodisponibilidade oral, riscos de toxicidade e metabolismo frente ao CYP 450. Neste sentido, as moléculas resultantes de tais etapas totalizaram em 7 e diante de seus promissores resultados, estas moléculas foram submetidas a docagem molecular, frente as 4 principais proteínas envolvidas no ciclo de replicação do influenza A, a citar: canal M2, hemaglutinina, neuraminidase e RNA polimerase. Com tais resultados, no geral todas as moléculas apresentaram ótimas interações frente as 4 principais proteínas do influenza A, com destaque, para a molécula HER03, que demonstrou ser um potencial candidato a fármaco atuante em múltiplos alvos, tendo em vista resultantes que apresentou scores de energias de interação superior a todos os fármacos controle e para todas as 4 proteínas envolvidas no ciclo de replicação do influenza A. Diante de tais resultados, foi demonstrado que das 986 moléculas naturais, 7 apresentaram potenciais para serem candidatos a fármacos frente ao influenza A, com destaque para a molécula HER03, que apresentou promissores e potenciais resultados para ser uma candidata a fármaco anti influenza A atuante em múltiplos alvos.Universidade Federal da ParaíbaBrasilFarmacologiaPrograma de Pós-Graduação em Produtos Naturais e Sintéticos BioativosUFPBScotti, Lucianahttp://lattes.cnpq.br/6420461345651715Medeiros, Herbert Igor Rodrigues de2022-03-31T18:00:18Z2021-12-292022-03-31T18:00:18Z2021-12-06info:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/masterThesishttps://repositorio.ufpb.br/jspui/handle/123456789/22624porAttribution-NoDerivs 3.0 Brazilhttp://creativecommons.org/licenses/by-nd/3.0/br/info:eu-repo/semantics/openAccessreponame:Biblioteca Digital de Teses e Dissertações da UFPBinstname:Universidade Federal da Paraíba (UFPB)instacron:UFPB2022-04-04T14:10:32Zoai:repositorio.ufpb.br:123456789/22624Biblioteca Digital de Teses e Dissertaçõeshttps://repositorio.ufpb.br/PUBhttp://tede.biblioteca.ufpb.br:8080/oai/requestdiretoria@ufpb.br|| diretoria@ufpb.bropendoar:2022-04-04T14:10:32Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB)false |
dc.title.none.fl_str_mv |
Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A |
title |
Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A |
spellingShingle |
Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A Medeiros, Herbert Igor Rodrigues de Influenza A Multitarget Química medicina Docagem molecular Medicinal chemistry Molecular docking CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
title_short |
Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A |
title_full |
Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A |
title_fullStr |
Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A |
title_full_unstemmed |
Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A |
title_sort |
Planejamento e desenvolvimento racional de candidatos a fármacos inibidores de Influenza A |
author |
Medeiros, Herbert Igor Rodrigues de |
author_facet |
Medeiros, Herbert Igor Rodrigues de |
author_role |
author |
dc.contributor.none.fl_str_mv |
Scotti, Luciana http://lattes.cnpq.br/6420461345651715 |
dc.contributor.author.fl_str_mv |
Medeiros, Herbert Igor Rodrigues de |
dc.subject.por.fl_str_mv |
Influenza A Multitarget Química medicina Docagem molecular Medicinal chemistry Molecular docking CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
topic |
Influenza A Multitarget Química medicina Docagem molecular Medicinal chemistry Molecular docking CNPQ::CIENCIAS BIOLOGICAS::FARMACOLOGIA |
description |
RNA viruses have been a major problem for the entire world, given their easy replication, mutation and transmission. Specifically, influenza A is an RNA virus responsible for a high number of deaths, whether acting alone or aggravating several existing pathological conditions. Given the situation that this virus brings to the population and taking into account the few drugs used for the treatment of influenza A, it is extremely important to search for drug candidates that do not have as many side effects and that are effective for it, in alternative to current treatments, stressing the importance of candidates that act on multiple targets (multitarget), seeking through these, more effective and promising drugs, since, among the main advantages, it has the ability to block more than one target, obtaining better effectiveness and strength profiles. Thus, medicinal chemistry, through the use of computational tools, has been essential in the drug planning process, as it allows the optimization of time and operating costs. Associated with this, the growing number of cases resulting from endemic diseases, such as influenza A, has encouraged funding agencies to invest in research for the development of molecules that could be used in the treatment of such diseases. Thus, the aim of the present work was to propose natural molecules with potential anti-influenza A activity, predicted by a consensus analysis of three biological activity prediction models and analyzed by a hybrid virtual screening. In view of this, the database of 986 natural molecules were screened, first, through consensus analysis from 3 predictive models of biological activity, which resulted in only 36 molecules predicted to be active for influenza A and with excellent percentage of reliability, resulting from the construction of the 3 predictive models. Subsequently, these molecules were subjected to analyzes of the profile of absorption and oral bioavailability, risks of toxicity and metabolism against CYP 450. Molecular docking, against the 4 main proteins involved in the replication cycle of influenza A, namely: M2 channel, hemagglutinin, neuraminidase and RNA polymerase. With such results, in general all molecules showed excellent interactions against the 4 main proteins of influenza A, with emphasis on the HER03 molecule, which proved to be a potential drug candidate acting on multiple targets, considering the results that presented scores of interaction energies higher than for all control drugs and for all 4 proteins involved in the influenza A replication cycle. In view of these results, it was demonstrated that of the 986 natural molecules, 7 had potential to be drug candidates against influenza A, highlighting the HER03 molecule, which showed promising and potential results to be a candidate for an anti-influenza A drug acting on multiple targets. |
publishDate |
2021 |
dc.date.none.fl_str_mv |
2021-12-29 2021-12-06 2022-03-31T18:00:18Z 2022-03-31T18:00:18Z |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
dc.type.driver.fl_str_mv |
info:eu-repo/semantics/masterThesis |
format |
masterThesis |
status_str |
publishedVersion |
dc.identifier.uri.fl_str_mv |
https://repositorio.ufpb.br/jspui/handle/123456789/22624 |
url |
https://repositorio.ufpb.br/jspui/handle/123456789/22624 |
dc.language.iso.fl_str_mv |
por |
language |
por |
dc.rights.driver.fl_str_mv |
Attribution-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nd/3.0/br/ info:eu-repo/semantics/openAccess |
rights_invalid_str_mv |
Attribution-NoDerivs 3.0 Brazil http://creativecommons.org/licenses/by-nd/3.0/br/ |
eu_rights_str_mv |
openAccess |
dc.publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
publisher.none.fl_str_mv |
Universidade Federal da Paraíba Brasil Farmacologia Programa de Pós-Graduação em Produtos Naturais e Sintéticos Bioativos UFPB |
dc.source.none.fl_str_mv |
reponame:Biblioteca Digital de Teses e Dissertações da UFPB instname:Universidade Federal da Paraíba (UFPB) instacron:UFPB |
instname_str |
Universidade Federal da Paraíba (UFPB) |
instacron_str |
UFPB |
institution |
UFPB |
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Biblioteca Digital de Teses e Dissertações da UFPB |
collection |
Biblioteca Digital de Teses e Dissertações da UFPB |
repository.name.fl_str_mv |
Biblioteca Digital de Teses e Dissertações da UFPB - Universidade Federal da Paraíba (UFPB) |
repository.mail.fl_str_mv |
diretoria@ufpb.br|| diretoria@ufpb.br |
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1801842990948286464 |