QSAR-Driven Discovery of Novel Chemical Scaffolds Active against Schistosoma mansoni

Abstract

Schistosomiasis is a neglected tropical disease that affects millions of people worldwide. Thioredoxin glutathione reductase of Schistosoma mansoni (SmTGR) is a validated drug target that plays a crucial role in the redox homeostasis of the parasite. We report the discovery of new chemical scaffolds against S. mansoni using a combi-QSAR approach followed by virtual screening of a commercial database and confirmation of top ranking compounds by in vitro experimental evaluation with automated imaging of schistosomula and adult worms. We constructed 2D and 3D quantitative structure–activity relationship (QSAR) models using a series of oxadiazoles-2-oxides reported in the literature as SmTGR inhibitors and combined the best models in a consensus QSAR model. This model was used for a virtual screening of Hit2Lead set of ChemBridge database and allowed the identification of ten new potential SmTGR inhibitors. Further experimental testing on both shistosomula and adult worms showed that 4-nitro-3,5-bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole (LabMol-17) and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}-1,2,5-oxadiazole (LabMol-19), two compounds representing new chemical scaffolds, have high activity in both systems. These compounds will be the subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents.

Discovery of New Anti-Schistosomal Hits by Integration of QSAR-Based Virtual Screening and High Content Screening

“…62,63 HCS microscopes are able to capture high resolution images of live organisms in quick succession, a feature that has been explored to evaluate phenotypic and motility changes in schistosomula 64 or adult worms. 65,66 …”

“…Previously, we have demonstrated the successful application of this platform in identification of potent antischistosomal hit compounds. 65,66 In this study, four compounds ( 1 – 4 ) were screened at 0.1–100 μ M concentrations for incubation times varying from 0 h (immediately after compound addition to culture medium) to 72 h.…”

A multi-dimensional, time-lapse, high content screening platform applied to schistosomiasis drug discovery

“…The live imaging platform described here can be incorporated into a drug discovery pipeline upstream of ex vivo phenotypic screens of the adult schistosomes and rodent models of infection [14]. Recent advances in the image-based quantification of adult schistosome motility [31,32] have demonstrated the ability to quantify motion and could mesh seamlessly with the workflow described here. The platform will complement other advances relating to schistosome biology, including gene expression profiling [33], metabolomics [34], and CRISPR/Cas9 [35], that together will improve our ability to Notably, the two approved anti-schistosomal drugs, PZQ and metrifonate, do not induce significant degeneracy under these conditions.…”

On the Virtues of Automated Quantitative Structure–Activity Relationship: The New Kid on the Block

“…The selection includes from a single series of compounds to a few classes for the same target. Learning sets varied from 35 to 255 compounds for a defined biochemical target (in parenthesis) related to the following diseases: Alzheimer's (hBACE1) [45], asthma (CRTh2) [46], cardiovascular (ABHD6) [47], Chagas' (cruzain) [48], diabetes (PTP1B) [49], malaria (PfDHODH) [50], and schistosomiasis (SmTGR) [51]. All examples represent recent and validated models.…”