Predição das propriedades físico-químicas, farmacocinéticas e de toxicidade de substâncias bioativas no combate da Doença de Chagas

Abstract

Currently, the treatment of Chagas disease is limited to two drugs, nifurtimox and benzonidazole, which have limited efficacy and cause significant side effects such as nausea, weight loss and neuropsychiatric effects. Moreover, according to the World Health Organization, these drugs are not effective at all stages of the disease, highlighting the need to develop new therapeutic options. In this study, we identified new therapeutic options for Chagas disease through the analysis of six drug candidates: Posaconazole (POS), CHEMBL3104525, CHEMBL91704, CHEMBL193804 (BZTS), isoxazole analog and a 4-arylaminonoline-3- carbonitrille derivative (DerM). We evaluated 40 physicochemical descriptors and ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties to determine the feasibility of each candidate using prediction tools such as admetlab2.0, admetSAR, preADMET, pkCSM and PredHerg. During the study, Posaconazole and CHEMBL91704 achieved unfavorable ADMET results, while CHEMBL3104525, CHEMBL193804 and the isoxazole analog stood out for being non-cardiotoxic. However, only the molecule CHEMBL193804 met all medicinal chemistry rules, positioning it as the most promising candidate for the treatment of Chagas disease. These results indicate that CHEMBL193804 has more adequate pharmacokinetic properties and lower toxic potential, making it potentially safer, with lower risk of adverse effects. Subsequently, we performed the evaluation of the biological activity spectrum of the target protein, Cruzain (RCPDB id: 4klb), evidencing CHEMBL193804 (BZTS) as a promising candidate for production and commercialization, by means of validated computational tools. In addition, the analysis of the binding mode and description of intermolecular interactions can provide relevant information to guide the development of new drugs, aiming to address the aforementioned issues.