Novel chemical scaffolds against Schistosoma mansoni discovered by combi-QSAR, virtual screening, and confirmed by experimental evaluation with automated imaging

Background: 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. Results: 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 in a virtual screen of a commercial database and allowed the identification of ten new potential SmTGR inhibitors. The latter were screened on schistosomula and two active compounds were further evaluated on adult worms. Conclusions: We succeed to develop predictive virtual screening tool based on 2D and 3D QSAR models. After prioritizing virtual screening hits, high activity of two compounds representing new chemical scaffolds, 4-nitro-3,5bis(1-nitro-1H-pyrazol-4-yl)-1H-pyrazole and 3-nitro-4-{[(4-nitro-1,2,5-oxadiazol-3-yl)oxy]methyl}1,2,5-oxadiazole (LabMol-17 and LabMol-19, respectively) was experimentally validated. These compounds will be subjects for additional testing and, if necessary, modification to serve as new schistosomicidal agents. Defined key terms Hologram quantitative structure-activity relationship (HQSAR): 2D quantitative structure-activity relationship (QSAR) approach based on a special type of structural fingerprints, also known as a molecular hologram, where information is used as an independent variable during calculations. Comparative molecular field analysis (CoMFA): 3D QSAR approach based on the calculation of molecular interaction fields between aligned molecules and a defined probe atom placed in different intersections of a lattice box. It uses the principle that most ligand-target interactions are noncovalent and can be described by steric and electrostatic fields. Comparative molecular similarity indices analysis (CoMSIA): 3D QSAR approach based on the calculation of molecular similarity indices between aligned molecules and a probe atom placed in different intersections of a lattice box. In addition to steric and electrostatic fields, it calculates hydrophobic, Hbond donor and acceptor fields. High content screening: A high-throughput phenotypic screening approach relying on automated microscopy followed by multiparametric computational image analysis.