Cestodes' FABPs: Ligand-based virtual screening and drug repurposing from public libraries

Abstract

Echinococcosis and cysticercosis are listed among WHO’s list of Neglected tropical diseases (NTD’s), affecting people in tropical and subtropical areas. Echinococcus granulosus and Echinococcus multilocularis are the causative agents of cystic and alveolar echinococcosis, respectively, while Taenia solium is the parasitic agent involved in cysticercosis. In general, cestodes present an incomplete lipid metabolism lacking many enzymes involved in their biosynthesis, so they must obtain these molecules from their hosts. In this sense, Fatty Acid Binding Proteins (FABPs) have been proposed as essential for the life cycle of cestodes since they are relevant in the traffic and delivery of lipids. Based on the target repurposing paradigm, we have generated ligand-based models to identify drug repurposing perspectives for the treatment of echinococcocis and cysticercosis. Taking into consideration the structural similarity between human and cestodes FABPs, we compiled from literature 288 compounds whose binding ability against human-aFABP had been experimentally established by fluorescence displacement assays. Compounds with IC50 values below 10 uM were labeled as active and above 20 uM as inactive, thus obtaining a dataset of 187 actives and 101 inactives. This dataset was then splitted into a training and a test set using iRaPCA clustering method. We generated 3000 linear models from our training set using a combination of feature bagging and forward stepwise feature selection; these were validated using Leave Group Out crossvalidation and Y-Randomization and tested against the test set. Moreover, we applied a selective ensemble learning approach to increase the predictive ability and robustness, as verified in retrospective screens performance. The best model ensemble was applied in a virtual screening campaign of several public compound libraries, obtaining 106 silico hit compounds. These compounds will be tested in vitro against cestodes’ FABPs isoforms.