Introduction: Schistosomiasis is a neglected tropical disease caused by trematode parasites of the genus Schistosoma, mainly Schistosoma mansoni (Sambon, 1907)[1]. This disease affects more than 250 million people worldwide, particularly in Africa and South America, and is responsible for approximately 70 million Disability Adjusted Life Years (DALYs)[2]. The current treatment for schistosomiasis has a limited range of options, and the most effective medicines currently available, praziquantel and oxamniquine, have several limitations. These include low efficacy in treating acute schistosomiasis and against early-stages S. mansoni infections, drug resistance, and no ability in preventing reinfection[3]. These obstacles, combined with the high prevalence of infected individuals, create an urgent demand for the development of new drugs for schistosomiasis[4].
Aims: The aim of this study was to conduct a virtual screening of alkaloids from the Fabaceae family to investigate their potential anti-Schistosoma mansoni activity.
Methods: The molecules for this study were selected through a literature review using the Web of Science database. The descriptors “Alkaloids” and “Fabaceae” were used, and articles published between 2020 and 2021 were selected. Before the molecular docking, redocking step was performed and the root-mean-square deviation (RMSD) calculated, using Molegro Virtual Docker v6.0.1, applying the standard settings. Three target structures were obtained from the RCSB Protein Data Bank: histone deacetylase 8 (HDAC8) (PDB: 4BZ8), complexed with the inhibitor J1038; S. mansoni sulfotransferase (PDB: 4MUB), complexed with oxamniquine; and thioredoxin glutathione reductase (TGR) (PDB: 6FTC), complexed with the inhibitor 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (EPE).
Results and Discussion: The molecular docking was performed using various targets based on their roles in schistosomiasis, and all the calculated RMSD values were below 2.0 Å. The first target selected was S. mansoni sulfotransferase, which can interact with oxamniquine and interfere with the macromolecular structure of the parasite[5]. In the simulations involving sulfotransferase, 39 molecules obtained better scores than the sulfotransferase-oxamniquine complex (-77,552 kJ). The top five compounds in this simulation were the molecules identified as A27 (-176.818 kJ), A35 (-170.241 kJ), A31 (-164.994 kJ), A16 (-150.723 kJ), and A28 (-147.513 kJ). The second target, HDCA8, is a protein responsible for gene expression of survival factors in both human and parasite organisms. There are various types of HDACs, but it has been observed that human HDAC8 has lower expression compared to other HDACs6. This makes HDAC8 a more specific target for acting on the parasite, thereby limiting potential adverse effects[6]. The molecular docking in this system showed that out of the total of 55 molecules, 29 achieved better MolDock scores compared to the J1038-HDAC8 complex (-91,502 kJ). The five best results were obtained from the simulations with molecules A35 (-174.763 kJ), A27 (-171.701 kJ), A31 (-169.736 kJ), A16 (-158.694 kJ), A28 (-145.399 kJ). Lastly, the TGR is the main antioxidant enzyme in the parasite and is considered an important target for new drugs against S. mansoni[7]. In the simulations with TGR, 52 molecules achieved better scores in comparison to the TGR-EPE complex (-44.06 kJ). These compounds are A42 (-146.906 kJ), A40 (-145.267kJ), A41 (-143.952 kJ), A3 (-135.629 kJ), A16 (-131.712 kJ). These results demonstrate that the majority of selected alkaloids obtained better MolDock scores than the reference ligands, indicating the potential of these molecules in the development of new drugs for treating schistosomiasis. Among all the alkaloids, molecule A16 (julisprosopine) showed significant results in all three selected targets when compared to the PDB ligands: sulfotransferase-oxamniquine (-77,552 kJ) and A16 (-150.723 kJ); J1038-HDAC8 (-91,502 kJ) and A16 (-158.694 kJ); TGR-EPE complex (-44.06 kJ) and A16 (131.712kJ). Juliprosopine is an indolizidine alkaloid that has already been tested against parasites from the genus Plasmodium, obtaining excellent results in vivo[8]. However, in the literature, there are no studies in vivo, in vitro, or even in silico against Schistosoma mansoni. Thus, the present study introduces a molecule that has the potential to act as a multi-target drug in the aforementioned systems. However, further studies are necessary to confirm this activity.
Conclusion. In this study, 55 alkaloids from the Fabaceae family were selected to perform a molecular docking in order to verify a possible anti-Schistosoma mansoni activity. It was observed that most of the alkaloids obtained higher scores compared to the control ligands, especially the compound A16, juliprosopine, which achieved excellent results in all simulations, possibly indicating a multi-target mode of action. In this way, this work opens new opportunities for the development of new drugs to treat schistosomiasis.
References:
[1] Menezes, R. P. B., Viana, J. O., Muratov, E., Scotti, L., Scotti, M. T. (2022). Computer-Assisted Discovery of Alkaloids with Schistosomicidal Activity. Curr Issues Mol Biol, 44(1):383-408. doi: 10.3390/cimb44010028.
[2] Ogongo, P., Nyakundi, R. K., Chege G. K., Ochola, L (2022). The Road to Elimination: Current State of Schistosomiasis Research and Progress Towards the End Game. Front. Immunol. 13:846108. doi:10.3389/fimmu.2022.846108.
[3] Molehin, A. J. (2020) Current Understanding of Immunity Against Schistosomiasis: Impact on Vaccine and Drug Development. Research and Reports in Tropical Medicine, 11, 119-128, DOI: 10.2147/RRTM.S274518.
[4] Caffrey, C. R., El?Sakkary, N., Mäder, P., Krieg, R., Becker, K., Schlitzer, M., … Grevelding, C. G. (2019). Drug Discovery and Development for Schistosomiasis. Methods and Principles in Medicinal Chemistry, 187–225. doi:10.1002/9783527808656.ch8.
[5] Pica-Mattoccia, L., Carlini, D., Guidi, A., Cimica, V., Vigorosi, F., & Cioli, D. (2006). The schistosome enzyme that activates oxamniquine has the characteristics of a sulfotransferase. Memórias Do Instituto Oswaldo Cruz, 101, 307–312. https://doi.org/10.1590/S0074-02762006000900048.
[6] Simoben, C. V., Robaa, D., Chakrabarti, A., Schmidtkunz, K., Marek, M., Lancelot, J., Kannan, S., Melesina, J., Shaik, T. B., Pierce, R. J., Romier, C., Jung, M., & Sippl, W. (2018). A Novel Class of Schistosoma mansoni Histone Deacetylase 8 (HDAC8) Inhibitors Identified by Structure-Based Virtual Screening and In Vitro Testing. Molecules (Basel, Switzerland), 23(3), 566. https://doi.org/10.3390/molecules23030566
[7] Silvestri, I., Lyu, H., Fata, F., Boumis, G., Miele, A. E., Ardini, M., Ippoliti, R., Bellelli, A., Jadhav, A., Lea, W. A., Simeonov, A., Cheng, Q., Arnér, E. S. J., Thatcher, G. R. J., Petukhov, P. A., Williams, D. L., Angelucci, F. (2018). Fragment-Based Discovery of a Regulatory Site in Thioredoxin Glutathione Reductase Acting as "Doorstop" for NADPH Entry. ACS chemical biology, 13(8), 2190–2202. https://doi.org/10.1021/acschembio.8b00349
[8] Senol, F. S., Orhan, I., Kürkçüo?lu, M., Khan, M. H., Altintas, A., ?ener, B., & Ba?er, K. H. C. (2011). An in vitro approach to neuroprotective activity of Rosa damascena Mill., a medieval age traditional medicine used for memory enhancement. Planta Medica, 77(12), PM163.
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