Introduction: Toxoplasma gondii (Nicolle & Manceaux, 1908) is a parasitic protozoan responsible for causing a zoonotic infection known as toxoplasmosis. This parasite is renowned for its remarkable resilience, as it can infect a wide range of warm-blooded animals [1]. It is estimated that approximately 30% of the population carries T. gondii, and the reactivation of the infection in immunocompromised individuals can lead to severe physical and psychological symptoms [2]. The standard first-line treatment for toxoplasmosis involves a combination of three medications: pyrimethamine, sulfadiazine, and folinic acid [3]. Unfortunately, this treatment regimen is associated with various complications, including conditions like Stevens-Johnson syndrome, toxic epidermal necrolysis, and hepatic necrosis [4]. As a result, there is a pressing need for the exploration of new drugs that are both effective and have fewer side effects. Objective: This study aimed to assess the potential of Fabaceae alkaloids against Toxoplasma gondii through virtual screening. Methodology: To achieve this objective, we conducted a search in the Web of Science database using the keywords: "Fabaceae" AND "alkaloids" with no geographical restrictions within the timeframe of 2020-2021. Six articles were identified as valid, yielding a total of 54 molecules. Following the organization and optimization of these compounds, we subjected them to molecular docking using Molegro Virtual Docker software version 6.0.1. In this process, we analyzed three specific targets: calmodulin-domain protein kinase 1 (4M84) in complex with 5-amino-1-tert-butyl-3-(quinolin-2-yl)-1H-pyrazole-4-carboxamide, 1-deoxy-D-xylulose-5-phosphate reductoisomerase (3AU8) in complex with Nadph dihydro-nicotinamide-adenine-dinucleotide phosphate, and enoyl-acyl carrier reductase (2O2S) in complex with Triclosan, all obtained from the Protein Data Bank (PDB). It’s worth nothing that before the docking, the enzymes underwent the redocking process to calculate the values of their respective RMSDs. Results and Discussion: The conducted redocking demonstrated that none of the resulting RMSD values were greater than 2.0 Å, indicating that none of the three enzymes analyzed exceeded the acceptable threshold. The docking analysis of the 54 molecules revealed that, for the target 2O2S, 42 of them achieved a better score than the ligand, with energies ranging from -72.0924 to -166.004 kJ.mol-1, and Juliprosopine exhibiting the lowest energy. In the case of target 3AU9, 12 molecules demonstrated a lower binding energy compared to the ligand, with energies spanning from -109.722 to -174.223 kJ.mol-1, and Erythrivarine M having the lowest energy. Concerning target 4M84, 7 molecules exhibited better energy values than the ligand, with energies ranging from -119.854 to -169.983 kJ.mol-1, and Senecionine displaying the highest score. It is noteworthy that the molecule Integerrimine showed favorable interactions with all three enzymes used, suggesting that this compound may have a significant multi-target effect. Furthermore, it was observed that among the 15 molecules (the top 5 for each enzyme) with the best interactions, 13 of them shared a common central structure, consisting of two six-membered carbon rings, a benzene ring, and a five-membered ring with nitrogen as a heteroatom, connecting one of the two cyclohexane’s to the five-membered ring. Conclusion: In summary, the selected Fabaceae alkaloids generally exhibited low binding energies when compared to the ligands of the studied enzymes. This suggests that this group of compounds holds substantial potential for the development of new drugs to combat toxoplasmosis.
Acknowledgments: We express our gratitude to the funding organizations, including the National Council for Scientific and Technological Development (CNPq), the Coordination for the Improvement of Higher Education Personnel (CAPES), and the Federal University of Paraíba (UFPB), for their invaluable financial support.
References:
[1] Aguirre, A.A.; Longcore, T.; Barbieri, M.; Dabritz, H.; Hill, D.; Klein, P.N.; Sizemore, G.C. The One health approach to toxoplasmosis: Epidemiology, control, and prevention strategies. EcoHealth 2019, 16, 378–390.
[2] Tomita T, Mukhopadhyay D, Han B, Yakubu R, Tu V, Mayoral J, et al. Toxoplasma gondii matrix atingen 1 is a secreted immunomodulatory effector. mBio 12 (2021) 12(3):e00603-21. doi: 10.1128/mBio.00603-21.
[3] Dunay, I.R.; Gajurel, K.; Dhakal, R.; Liesenfeld, O.; Montoya, J.G. Treatment of Toxoplasmosis: Historical Perspective, Animal Models, and Current Clinical Practice. Clin. Microbiol. Rev. 2018, 31.
[4] Ardabili, S.; Kohl, J.; Gül, G.; Hodel, M. What obstetricians should be aware of: Serious side effects of antibiotic toxoplasmosis treatment in pregnancy. BMJ Case Rep. 2021, 14, e240809.
Comissão Organizadora
Francisco Mendonça Junior
Pascal Marchand
Teresinha Gonçalves da Silva
Isabelle Orliac-Garnier
Gerd Bruno da Rocha
Comissão Científica
Ricardo Olimpio de Moura
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