Alvos terapêuticos da obesidade e potencial in silico do inibidor de tripsina isolado de sementes de tamarindo como precursor de peptídeos inibidores de lipase

Abstract

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.