Chagas’ disease is an endemic disease caused by Trypanosoma cruzi, which affects more than eight million people, mostly in the Americas1. Chemotherapies currently used against T. cruzi are benznidazole and nifurtimox. These drugs, despite having effectiveness above 80% in the acute phase of the disease, present several problems mainly in the chronic phase where their effectiveness is limited, being necessary the search for new treatments is necessary for the control and elimination of this disease2,3. Sesquiterpene lactones (SLs) are an interesting group of secondary metabolites characteristic of Asteraceae that have presented a wide range of biological activities4,5.
In this work, from the ChEMBL database, we selected a diverse set of 4,452, 1,635 and 1,322 structures with tested activity against the three T. cruzi parasitic forms, amastigote, trypomastigote and epimastigote, respectively, to create random forest (RF) models with accuracy over 74% for cross-validation and test set. After, ligand-based virtual screening of the entire SLs of Asteraceae databank stored in SistematX (1,306 structures, http://sistematx.ufpb.br) was performed. Some common structural features are observed among the structures with highest probability values. In addition, a structure-based virtual screening was also carried out through molecular docking for the same set of SLs, using eight target proteins of T.cruzi: Cruzain, sterol 14α-demethylase, glyceraldehyde-3-phosphate dehydrogenase, Dihydrofolate Reductase-Thymidylate synthase, trans-sialidase, Histidyl-tRNA synthetase, spermidine synthase and Hypoxanthine phosphoribosyl transferase. Dimeric SLs have the highest active probability values in seven T. cruzi proteins. Enhydrofolin and Uvedafolin being those with the two lowest energy values in five of them.
Finally, using combined approaches of ligand-based and structure-based virtual screening we verified potentially active compounds and established a possible mechanism of action. Some structures that previously had presented a high active probability in ligand-based virtual screening appear as interesting multitarget structures (acting in two or more proteins of T. cruzi) for each parasitic form, e.g. 8-α-isovaleryloxy-8-desacyl-viguestenin, that presents the highest combined probability (pc) against Histidyl-tRNA synthetase and spermidine synthase.

References

1 J.A. Pérez-Molina, I. Molina, Lancet 2017
2 C.J. Salomon, J. Pharm. Sci. 2012, 101, 888-894;
3 P.M. Guedes, G.K. Silva, F.R. Gutierrez, J.S. Silva, Expert Rev. Anti-Infect. Ther. 2011, 9, 609
4 C. Herrera Acevedo, L. Scotti, M. Feitosa Alves, M.F.M.Diniz, M. Scotti, Molecules 2017, 22, 79
5 T. J. Schmidt, A. M. Nour, S. A. Khalid, M. Kaiser, R. Brun, Molecules 2009, 14, 2062-2076.