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...
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| Formato: | Dissertação |
| Idioma: | pt_BR |
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Universidade Federal do Rio Grande do Norte
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| Endereço do item: | https://repositorio.ufrn.br/handle/123456789/53152 |
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| Resumo: | 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. |
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