Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase
Obesity is a multifactorial disease with numerous therapeutic targets, which is a risk factor for the development of several non-communicable chronic diseases. Therefore, this study aimed to identify therapeutic targets for obesity through a systematic review (SR) of in silico evaluations, and to...
Na minha lista:
| Autor principal: | |
|---|---|
| Outros Autores: | |
| Formato: | Dissertação |
| Idioma: | pt_BR |
| Publicado em: |
Universidade Federal do Rio Grande do Norte
|
| Assuntos: | |
| Endereço do item: | https://repositorio.ufrn.br/handle/123456789/53152 |
| Tags: |
Adicionar Tag
Sem tags, seja o primeiro a adicionar uma tag!
|
| id |
ri-123456789-53152 |
|---|---|
| record_format |
dspace |
| institution |
Repositório Institucional |
| collection |
RI - UFRN |
| language |
pt_BR |
| topic |
Agentes antiobesidade Simulação por computador Terapêutica Hidrolases Tamarindus indica L. CNPQ::CIENCIAS DA SAUDE::NUTRICAO |
| spellingShingle |
Agentes antiobesidade Simulação por computador Terapêutica Hidrolases Tamarindus indica L. CNPQ::CIENCIAS DA SAUDE::NUTRICAO Medeiros, Wendjilla Fortunato de Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase |
| description |
Obesity is a multifactorial disease with numerous therapeutic targets,
which is a risk factor for the development of several non-communicable chronic
diseases. Therefore, this study aimed to identify therapeutic targets for obesity
through a systematic review (SR) of in silico evaluations, and to analyze the
potential of peptides derived from the theoretical model of the purified trypsin
inhibitor from tamarind seeds (ITTp 56/287) to interact in silico with Human
Pancreatic Lipase (HPL). At first, the SR was guided by the following research
question:(What therapeutic targets have been used in in silico analysis for the
treatment of obesity?) based on the PECo acronym (P, problem; E, exposure; Co,
context). "The SR protocol was developed and registered in PROSPERO
(CRD42022353808) according to the Preferred Reporting Items Checklist for
Systematic Review and Meta-Analysis Protocols (PRISMA-P), and the PRISMA
was followed for the systematic review. The study selection was performed
according to the eligibility criteria, in the following databases: PubMed,
ScienceDirect, Scopus, Web of Science, BVS, and EMBASE. "The search
strategy returned 938 articles, of which 9 were included in the study, resulting in
the identification of six therapeutic targets studied in silico and re-evaluated in
vivo. These targets consisted of five experimental structures and one theoretical
model. Molecular docking was employed in the studies as the methodology, and
the most studied target was Human Pancreatic Lipase (HPL) (n=4). The lack of
methodological details led over 50% of the studies to be classified as "uncertain
risk of bias" in seven out of the eleven points evaluated. For the computer
simulation studies, in silico hydrolysis of ITTp 56/287 was performed (ExPASy
PeptideCutter), and five peptides were selected for modeling (trRosetta),
evaluation of bioactivity potential (PeptideRanker), cell penetration (CellPPD),
and half-life (HLP). Molecular docking studies were conducted between ITTp
56/287, the selected peptides, and the drug Orlistat (control) to identify the
interaction with LPH (PDB ID: 1LPB). The peptide (PEP2) selected for Molecular Dynamics (MD) study with LPH, conducted on GROMACS software, was
classified as potentially bioactive, exhibited high stability, longer half-life in
simulated intestinal environment (1.863 seconds) and interacted in the docking
study (docking score -136.13) with amino acids of interest present in the catalytic
pocket and hydrophobic lid of the target. In the MD simulation between PEP2 and
LPH, a potential interaction energy (PIE) of -628.44 Kj.mol-1 was obtained, where
four amino acid residues of PEP2 stood out as responsible for 74.3% of the PIE
(Asp3, Ser1, Asp4, and Asp5). As observed, ITTp can be a source of new
bioactive peptides, particularly PEP2, which proved to be a promising candidate
for further study in the field of peptide-based therapy as an inhibitor of LPH,
providing a basis for future in vitro and in vivo studies. Therefore, given the
persistence of obesity as a public health problem and the failure of its control, the
importance of combining in silico methodologies in the study of potential drug
targets, as well as in the search for new therapeutic agents, is evident. |
| author2 |
Morais, Ana Heloneida de Araújo |
| author_facet |
Morais, Ana Heloneida de Araújo Medeiros, Wendjilla Fortunato de |
| format |
masterThesis |
| author |
Medeiros, Wendjilla Fortunato de |
| author_sort |
Medeiros, Wendjilla Fortunato de |
| title |
Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase |
| title_short |
Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase |
| title_full |
Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase |
| title_fullStr |
Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase |
| title_full_unstemmed |
Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase |
| title_sort |
alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase |
| publisher |
Universidade Federal do Rio Grande do Norte |
| publishDate |
2023 |
| url |
https://repositorio.ufrn.br/handle/123456789/53152 |
| work_keys_str_mv |
AT medeiroswendjillafortunatode alvosterapeuticosdaobesidadeepotencialinsilicodoinibidordetripsinaisoladodesementesdetamarindocomoprecursordepeptideosinibidoresdelipase AT medeiroswendjillafortunatode therapeutictargetsofobesityandinsilicopotentialoftrypsininhibitorsisolatedfromtamarindseedsasprecursoroflipaseinhibitorspeptides |
| _version_ |
1773961582755184640 |
| spelling |
ri-123456789-531522023-07-07T22:39:27Z Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase Therapeutic targets of obesity and in silico potential of trypsin inhibitors isolated from tamarind seeds as precursor of lipase inhibitors peptides Medeiros, Wendjilla Fortunato de Morais, Ana Heloneida de Araújo http://lattes.cnpq.br/5685354458590232 https://orcid.org/0000-0002-6460-911X http://lattes.cnpq.br/1233944493334651 Serquiz, Alexandre Coelho Vieira, Davi Serradella https://orcid.org/0000-0001-8353-6262 http://lattes.cnpq.br/4185159774625471 Agentes antiobesidade Simulação por computador Terapêutica Hidrolases Tamarindus indica L. CNPQ::CIENCIAS DA SAUDE::NUTRICAO Obesity is a multifactorial disease with numerous therapeutic targets, which is a risk factor for the development of several non-communicable chronic diseases. Therefore, this study aimed to identify therapeutic targets for obesity through a systematic review (SR) of in silico evaluations, and to analyze the potential of peptides derived from the theoretical model of the purified trypsin inhibitor from tamarind seeds (ITTp 56/287) to interact in silico with Human Pancreatic Lipase (HPL). At first, the SR was guided by the following research question:(What therapeutic targets have been used in in silico analysis for the treatment of obesity?) based on the PECo acronym (P, problem; E, exposure; Co, context). "The SR protocol was developed and registered in PROSPERO (CRD42022353808) according to the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and the PRISMA was followed for the systematic review. The study selection was performed according to the eligibility criteria, in the following databases: PubMed, ScienceDirect, Scopus, Web of Science, BVS, and EMBASE. "The search strategy returned 938 articles, of which 9 were included in the study, resulting in the identification of six therapeutic targets studied in silico and re-evaluated in vivo. These targets consisted of five experimental structures and one theoretical model. Molecular docking was employed in the studies as the methodology, and the most studied target was Human Pancreatic Lipase (HPL) (n=4). The lack of methodological details led over 50% of the studies to be classified as "uncertain risk of bias" in seven out of the eleven points evaluated. For the computer simulation studies, in silico hydrolysis of ITTp 56/287 was performed (ExPASy PeptideCutter), and five peptides were selected for modeling (trRosetta), evaluation of bioactivity potential (PeptideRanker), cell penetration (CellPPD), and half-life (HLP). Molecular docking studies were conducted between ITTp 56/287, the selected peptides, and the drug Orlistat (control) to identify the interaction with LPH (PDB ID: 1LPB). The peptide (PEP2) selected for Molecular Dynamics (MD) study with LPH, conducted on GROMACS software, was classified as potentially bioactive, exhibited high stability, longer half-life in simulated intestinal environment (1.863 seconds) and interacted in the docking study (docking score -136.13) with amino acids of interest present in the catalytic pocket and hydrophobic lid of the target. In the MD simulation between PEP2 and LPH, a potential interaction energy (PIE) of -628.44 Kj.mol-1 was obtained, where four amino acid residues of PEP2 stood out as responsible for 74.3% of the PIE (Asp3, Ser1, Asp4, and Asp5). As observed, ITTp can be a source of new bioactive peptides, particularly PEP2, which proved to be a promising candidate for further study in the field of peptide-based therapy as an inhibitor of LPH, providing a basis for future in vitro and in vivo studies. Therefore, given the persistence of obesity as a public health problem and the failure of its control, the importance of combining in silico methodologies in the study of potential drug targets, as well as in the search for new therapeutic agents, is evident. Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES A obesidade é uma doença multifatorial com inúmeros alvos terapêuticos, a qual consiste em um fator de risco para o desenvolvimento de diversas doenças crônicas não transmissíveis. Sendo assim, este estudo objetivou identificar os alvos terapêuticos da obesidade, avaliados in silico, por meio de uma revisão sistemática (RS) e analisar o potencial de peptídeos derivados do modelo teórico do inibidor de tripsina purificado de sementes de tamarindo (ITTp 56/287) interagirem in silico com a Lipase Pancreática Humana (LPH). Primeiramente a RS foi norteada pela seguinte pergunta de pesquisa “Quais os alvos terapêuticos empregados no tratamento da obesidade em estudos in sílico?”, baseada no acrônimo PECo (P, problema; E, exposição; Co, contexto). O protocolo de RS foi desenvolvido e registrado no PROSPERO (CRD42022353808) conforme o Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis Protocols (PRISMA-P) e para a RS foi seguido o PRISMA. A seleção dos estudos foi realizada em concordância com os critérios de elegibilidade, nas seguintes bases de dados: PubMed, ScienceDirect, Scopus, Web of Science, BVS e EMBASE. A estratégia de busca retornou 938 artigos, 9 foram incluídos na pesquisa, resultando na identificação de seis alvos terapêuticos estudados in silico e reavaliados in vivo, sendo cinco estruturas experimentais e teórica. A metodologia utilizada nos estudos foi a do docking molecular e o alvo mais estudado foi a Lipase Pancreática Humana (LPH) (n = 4). A ausência de detalhes metodológicos levou mais de 50% dos trabalhos a serem classificados com “risco de viés incerto” em sete dos onze pontos avaliados. Para os estudos de simulação computacional foi realizada a hidrólise in sílico do ITTp 56/287 (ExPASy PeptideCutter), sendo selecionados cinco peptídeos para modelagem (trRosetta), avaliação do potencial de bioatividade (PeptideRanker), penetração celular (CellPPD) e meia-vida (HLP). Estudos de docking molecular foram conduzidos entre o ITTp 56/287, os peptídeos selecionados e o fármaco Orlistate (controle) para identificação da interação com a LPH (PDB ID:1LPB). O peptídeo (PEP2) que seguiu para o estudo de Dinâmica Molecular (DM) com a LPH, conduzido no software GROMACS, foi classificado como potencialmente bioativo, apresentou alta estabilidade, maior meia-vida em ambiente intestinal simulado (1.863 segundos) e interagiu no estudo de docking (docking score -136.13) com aminoácidos de interesse presentes no bolso catalítico e tampa hidrofóbica do alvo. Na DM entre o PEP2 e a LPH, obteve-se uma energia potencial de interação (EPI) de -628,44 kJ mol-1, onde se destacam quatro resíduos de aminoácidos do PEP2 que foram responsáveis por 74,3% da EPI (Asp3, Ser1, Asp4 e Asp5). Conforme verificado, o ITTp pode ser fonte de novos peptídeos bioativos, em especial o PEP2, que se mostrou um candidato promissor a ser estudado no campo da terapia baseada em peptídeos como inibidor de LPH, fornecendo base para futuros estudos in vitro e in vivo. Com isso, persistindo a obesidade como um problema de saúde pública e frente ao insucesso no controle, é evidente a importância da associação de metodologias in silico nos estudos de potenciais candidatos a alvos drogáveis, bem como na busca por novos agentes terapêuticos. 2023-07-07T22:38:44Z 2023-07-07T22:38:44Z 2023-05-25 masterThesis MEDEIROS, Wendjilla Fortunato de. Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase. Orientador: Ana Heloneida de Araújo Morais. 2023. 109f. Dissertação (Mestrado em Nutrição) - Centro de Ciências da Saúde, Universidade Federal do Rio Grande do Norte, Natal, 2023. https://repositorio.ufrn.br/handle/123456789/53152 pt_BR Acesso Aberto application/pdf Universidade Federal do Rio Grande do Norte Brasil UFRN PROGRAMA DE PÓS-GRADUAÇÃO EM NUTRIÇÃO |