Estudos de docking molecular de derivados da tiazolidina como potenciais inibidores da enzima cruzaína de trypanosoma cruz

Abstract

Chagas disease, also known as American trypanosomiasis, is a parasitic infection caused by the flagellate parasite Trypanosoma cruzi (T.cruzi) and constitutes one of the greatest public health problems in endemic regions, with devastating consequences in terms of morbidity and mortality human. The forms of treatment against the disease are quite limited and insufficient in all clinical aspects. Aiming at the development of novel antichagasic agents, various parasite proteins have been exploited as therapeutic targets. In this context, the enzyme cruzain, a cysteine protease involved in all stages of development and differentiation of T. cruzi and essential for the replication of the intracellular parasite, was selected for our studies, aiming at the identification of possible inhibitors. Thus, the objective of this work was to investigate the trypanocidal action of eight compounds of the thiazolidine class in silico, where molecular docking studies were carried out with the cross-enzyme target, using the crystallographic structure of PDB ID: 1U9Q, and the analysis of the properties that affect the absorption and distribution characteristics of these drug candidate compounds were evaluated throughthe pkCMS and SwissADME platforms in order to perform a comparison of the experimental results found in the work carried out by the Laboratory of Chemistry and Therapeutic Innovation (LQIT) of UFPE, with the theoretical results found in this work. As a result of the docking and analysis of the intermolecular interactions, it was observed that the protein-ligand complexes formed mainly occur through hydrophobic interactions, the compounds 5D (bromo-indole-, 3-4-dichloro) and 5G (bromo-indole-methylsulfanyl) which showed the highest interaction with cruzaine with binding energies of -8.24 and -8.16 kcal.mol -1, respectively. And that all ligands perform interactions with Cys25, an important residue that makes up the catalytic triad of the enzyme. It was verified that the results of the experimental tests used as a comparative study for the theoretical research of this work were not compatible with the complexes that presented higher interaction energy, since the focus of the in vitro tests was not necessarilythe cruzaine, therefore, tests of protein inhibition would be required. The pharmacokinetic profile of the compounds under study showed that they should have good absorption and distribution characteristics.