Abstract
Small-molecule compounds that have promising activity against macromolecular targets from Trypanosoma cruzi occasionally fail when tested in whole-cell phenotypic assays. This outcome can be attributed to many factors, including inadequate physicochemical and pharmacokinetic properties. Unsuitable physicochemical profiles usually result in molecules with a poor ability to cross cell membranes. Quantitative structure-activity relationship (QSAR) analysis is a valuable approach to the investigation of how physicochemical characteristics affect biological activity. In this study, artificial neural networks (ANNs) and kernel-based partial least squares regression (KPLS) were developed using anti-T. cruzi activity data for broadly diverse chemotypes. The models exhibited a good predictive ability for the test set compounds, yielding q2 values of 0.81 and 0.84 for the ANN and KPLS models, respectively. The results of this investigation highlighted privileged molecular scaffolds and the optimum physicochemical space associated with high anti-T. cruzi activity, which provided important guidelines for the design of novel trypanocidal agents having drug-like properties.
Highlights
Chagas’ disease, which is a neglected tropical disease caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America, where it is endemic [1]
The determinant role played by these properties was shown by the analysis of the weights that were attributed to each physicochemical descriptor at the hidden-layer neurons of the best artificial neural networks (ANNs) (Table 4)
A set of 363 structurally diverse compounds covering a broad interval of trypanocidal activity was used to build highly predictive Quantitative structure-activity relationship (QSAR) models
Summary
Chagas’ disease, which is a neglected tropical disease (as defined by the World Health Organization, WHO) caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America, where it is endemic [1]. Current chemotherapy for Chagas’ disease is limited to nifurtimox and benznidazole, which are two obsolete drugs identified in 1965 and 1971, respectively (Figure 1). These nitroheterocyclic compounds cause several adverse effects, such as weight loss, neurological damage, anorexia, dermatitis, depression, nausea, and gastrointestinal problems [3,4]. They lack effectiveness in the chronic phase of the disease. Given these drawbacks, novel, effective, and safe drugs for Chagas’ disease are urgently needed [5]
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