Predição in silico de alvos moleculares relacionados à toxicidade do desenvolvimento do antiparasitário moxidectina em organismos não alvo

Abstract

Brazil is the world's largest exporter of beef and chicken and ranks second in the production of these foods, according to the Ministry of Agriculture and Livestock (MAPA). Thus, there are many products used in the maintenance of these animals, among them, the endectocide moxidectin (MOX), which is used in the permanent management of ticks, lice and helminths. From an ecotoxicological perspective, these compounds can enter the environment and cause damage to non-target organisms, causing individual and/or ecosystem damage. Recently, MOX was shown to cause oxidative stress and delayed hatching in zebrafish embryos, signs of developmental toxicity (DT). Furthermore, its accumulation was also seen in the head and eye region of embryos, leading to the hypothesis that MOX could affect the development of the nervous system. In this sense, the present work sought to investigate the involvement of MOX with biological targets and pathways related to DT, through in silico approaches. To this end, network toxicology methodologies were used to predict molecular targets, and molecular docking and dynamics were used to analyze the interaction of the compound with the screened targets. The main targets found were components of the γ-secretase complex, a protein complex responsible for activating the Notch signaling pathway, which plays an important role in normal development and in the establishment of pathophysiological processes in the nervous system. The docking simulations attributed satisfactory binding energies of moxidectin with the catalytic subunits of γ-secretase (PS1 and PS2). Molecular dynamics showed that the target-MOX complex remained stable in an environment that simulates physiological conditions. Finally, dysfunction of cell signaling and protein regulation with negative effects on the development of the nervous system make up, at least in part, the toxic mode of action of MOX in zebrafish embryos.