Aspectos funcionais de peptídeos vegetais com efeito anti-inflamatório na obesidade e avaliação estrutural do inibidor de tripsina kunitz de sementes de tamarindo

Abstract

Subclinical inflammation in overweight and obesity alters several metabolic pathways, with positive reinforcement for accumulating more adipose tissue and alteration in energy metabolism. Several studies have evaluated the anti-inflammatory and immunomodulatory effects of hydrolyzed proteins and plant peptides, but it is necessary to explore the mechanisms of action of these effects. Thus, in the first chapter of this thesis, the narrative review presented the understanding of the mechanisms of action of hydrolyzed proteins and plant peptides on inflammation affected by excess adipose tissue. For this, a search was performed in the databases, selecting studies involving target metabolic pathways and responses of hydrolyzed proteins or peptides of plant origin. The mechanisms observed permeate the inhibition of the NF-kB pathway, reduction of oxidative stress, stimulation of the PI3K-AKT pathway and enzymes related to detoxification (superoxide dismutase and catalase), thus culminating in the reduction of inflammatory cytokines and adipokines, as well as the polarization of macrophages to the M2 phenotype. In the second chapter, the study in vitro and computer simulation (in silico) with the purified trypsin inhibitor of tamarind seeds (Tamarindus indica L.) (TTIp) is shown. This protein has been studied in vitro and in preclinical studies to treat obesity, its complications, and associated comorbidities. The TTIp was sequenced de novo by MALDI-TOF/TOF. Its modeling was obtained by homology, and the interaction with the trypsin enzyme (PDB ID 2PTN) was evaluated through molecular dynamics simulation (DM) under controlled conditions of temperature, pressure, and presence of water. 75 additional amino acid residues from the TTIp sequence were identified. The modeling by homology was performed by CONCOORD and validated by MolProbity, and the four best conformations of the modeling were submitted to DM. Conformation no. 287 of model no. 56 was selected, considering the RMSD analysis and the interaction energy (-301.0128 kcal.mol-1). Ile (54), Pro (57), Arg (59), Arg (63) and Glu (78) residues of ITTp showed lower interaction energy and, therefore, more significant interaction with the trypsin enzyme (PDB ID 2PTN). Among these, Arg residues (59 and 63) were mainly involved in its electrostatic binding mechanism. These results favor continuity of studies with the TTIp for applications in preclinical and clinical studies in the health area, contributing to the control of severe public health diseases, such as obesity. Finally, considering the potential therapeutic molecular targets in the inflammatory metabolic pathways for plant peptides in the treatment of obesity, revealed through the narrative review, sequencing, modeling and molecular dynamics of TTIp with trypsin, through studies in silico, this thesis deepens knowledge about TTIp and generates support for future studies.