Aplicação de metodologias in silico de predição de toxicidade de substâncias bioativas candidatas a fármacos para o tratamento da COVID-19

Abstract

COVID-19 is a viral disease caused by the coronavirus that has resulted in millions of deaths around the planet. Several drugs have been suggested andused for the treatment of COVID-19, many of which are used in treatment of other pathologies and proposes a pharmacological repositioning to mitigate the effects caused by the virus. Among the drugs used indiscriminately by the population are the so-called “covid kit” and two proposals for newer drugs such as molnupiravir and nirmatrelvir. The cocktail used in the covid kit has no proof of antiviral activity and neither shows benefit to the affected patients. These substances and their biotransformation products do not have fully established toxicity; studies on the potential harm caused by the improper use of them must be carried out. The research work involved the application of in silico methods in the study of biotransformation and prediction of potential toxic effects from substances used to fight the SARS-CoV-2 virus. The generation of unknown metabolites was determined by the software Biotransformer and by the assessment of small molecule metabolism in human tissue. The drugs were chloroquine, azithromycin and ivermectin (B1a/b) from the “covid kit”. The drugs and the generated products had the risk of mutagenic effects, tumorigenic, irritant and toxic to the reproductive system (Osiris Property Explorer), hepatotoxicity and genotoxicity (pKCSM) evaluated. The search for metabolites resulted in 17, 28, 35/38 biotransformation products for chloroquine, azithromycin and ivermectins (B1a/b), respectively. Chloroquine presented a risk of mutagenic, irritating, genotoxic and hepatotoxic effects. The 17 generated products showed mutagenic effect, and 11 irritating effects, being the acetaldehyde metabolite the most toxic in the parameters evaluated, especially causing hepatotoxicity. Azithromycin presented low theoretical risks of toxicity, excepting the risk of hepatotoxicity. 27 of its metabolites also showed this risk, with the exception of only one. Ivermectins had a potential hepatotoxic effect when used with the pKCSM, and the Osiris software did not show resolving ability in predicting toxicity for these compounds. The results indicate that the concomitant use of these drugs and their biotransformation generated products can potentiate the hepatotoxic effect predicted in these studies. This fact can be aggravated by the use of them over long periods of time. The prediction of biotransformation products and toxicity granted the obtainment of additional information to the literature about the toxicity of inappropriate use of the “covid kit”.