Application of Data-Centric Supervised Machine Learning to Predict Phenotypic Activity Against Clinically Relevant...

Background/Objectives: Chagas disease is a neglected tropical disease caused by the protozoan parasite Trypanosoma cruzi, which currently affects around 8 million people worldwide. The therapeutic arsenal against T. cruzi is so far limited to only two approved drugs, benznidazole and nifurtimox, that have considerable side effects and limited efficacy in the chronic stage of the disease. Here, we have resorted to supervised phenotypic machine learning models to explore drug repurposing opportunities and identify potential new therapeutic solutions for Chagas disease. Methods: More than 100,000 bioactivity data points were retrieved from ChEMBL and carefully curated according to the data-centric machine learning paradigm. After curation, two datasets comprising 344 compounds tested against T. cruzi Y strain trypomastigotes and 785 compounds tested against Tulahuen strain amastigotes were obtained and used to infer ensemble learning models with excellent average and early enrichment metrics in retrospective screening experiments (AUROC > 0.96 and EF_0.01 > 58). A prospective screening campaign was then performed on DrugBank and the Drug Repurposing Hub databases, submitting eight in silico hits for experimental confirmation. Results: Six of the in silico hits confirmed their predicted trypanocidal effects. Conclusions: We have built portable meta-classifiers capable of identifying small molecules with trypanocidal activity against amastigotes, the clinically most relevant stage of T. cruzi. The predictive ability of this meta-classifier was experimentally validated.