Do conhecimento à aplicação: triagem virtual e aplicação experimental de compostos fenólicos e de terpenos da família fabaceae para estratégias multialvo contra doenças tropicais negligenciadas e doenças virais emergentes

Abstract

Neglected diseases and emerging viral infections, such as that caused by SARS-CoV-2 the etiological agent of the COVID-19 pandemic (March 11, 2020, to May 5, 2023), pose a serious challenge to global public health, primarily affecting low-income populations and regions with poor infrastructure. The limited efficacy of existing therapies, often associated with high toxicity and the development of resistance to conventional drugs, underscores the need for new strategies in drug discovery. In this context, secondary metabolites from the Fabaceae family stand out as promising sources of bioactive molecules. This family is considered one of the most representative in the plant kingdom, being particularly rich in phenolic compounds and terpenoids, classes widely recognized for their broad spectrum of biological activities. Among the phenolic compounds, chalcones deserve special attention due to their structural diversity and pharmacological potential, including antiparasitic and antiviral properties. Similarly, terpenes especially those belonging to the triterpenoid class are abundant in Fabaceae species and have demonstrated significant effects against different pathogens. Based on this scenario, this Ph.D. thesis aimed to identify and propose new drug candidates through integrated strategies involving Cheminformatics, Medicinal Chemistry, virtual screening, and experimental validation. Initially, reviews were conducted on recent advances in rational drug design for neglected diseases, with an emphasis on multitarget compounds and key enzymes of parasite energy metabolism, such as succinate dehydrogenase. In the computational phase, in silico methodologies were applied, including pharmacophore modeling and QSAR, targeting phenolic and terpenoid derivatives from the Fabaceae family. Virtual screening was complemented by molecular docking and structure-activity relationship (SAR) analyses, prioritizing compounds with higher predicted biological activity. Among the main findings, chalcones with potent antimalarial action (Plasmodium falciparum, IC₅₀ < 10 μM, SI > 12) and triterpenoids with anti-SARS-CoV-2 activity were identified, particularly those from the Lupane series, with emphasis on betulinic acid, whose activity was confirmed in phenotypic assays, showing viral inhibition above 50% and cell viability above 70%. These results highlight the potential of integrating computational tools and experimental approaches to accelerate the discovery of new therapeutic candidates, contributing to the development of innovative strategies to combat tropical diseases and emerging viral infections.