A study by (Luechtefeld et al., 2018) described the development of a suite of in silico models, termed read-across structure activity relationships (RASAR), that have “balanced accuracies in the 80%–95% range across 9 health hazards with no constraints on tested compounds.” This work can be considered groundbreaking for apparently exceeding the most optimistic expectations for quantitative structure-activity relationship (QSAR) modeling accuracy, especially without restrictions on model applicability domains. Predictive in silico models have been facilitating replacement and reduction of animal testing in toxicology (Wold et al., 1985); however, it is also recognized that “these methods are not always reliable and must be assessed on their individual merit for the compound and context in question” (Cronin et al., 2017). It is widely acknowledged that QSAR and other in silico models should be subject to rigorous testing and validation (Dearden et al., 2009; Fourches et al., 2010, 2015; OECD, 2014; Tropsha, 2010). Thus, we were curious to understand what technological advances have enabled the RASAR models to achieve accuracy that, for the first time in the history of QSAR, was “outperforming animal tests reproducibility” (Luechtefeld et al., 2018).

The development of novel therapeutics is urgently required for diseases where existing treatments are failing due to the emergence of resistance. This is particularly pertinent for parasitic infections of the tropics and sub-tropics, referred to collectively as neglected tropical diseases, where the commercial incentives to develop new drugs are weak. One such disease is schistosomiasis, a highly prevalent acute and chronic condition caused by a parasitic helminth infection, with three species of the genus Schistosoma infecting humans. Currently, a single 40-year old drug, praziquantel, is available to treat all infective species, but its use in mass drug administration is leading to signs of drug-resistance emerging. To meet the challenge of developing new therapeutics against this disease, we developed an innovative computational drug repurposing pipeline supported by phenotypic screening. The approach highlighted several protein kinases as interesting new biological targets for schistosomiasis as they play an essential role in many parasite’s biological processes. Focusing on this target class, we also report the first elucidation of the kinome of Schistosoma japonicum, as well as updated kinomes of S. mansoni and S. haematobium. In comparison with the human kinome, we explored these kinomes to identify potential targets of existing inhibitors which are unique to Schistosoma species, allowing us to identify novel targets and suggest approved drugs that might inhibit them. These include previously suggested schistosomicidal agents such as bosutinib, dasatinib, and imatinib as well as new inhibitors such as vandetanib, saracatinib, tideglusib, alvocidib, dinaciclib, and 22 newly identified targets such as CHK1, CDC2, WEE, PAKA, MEK1. Additionally, the primary and secondary targets in Schistosoma of those approved drugs are also suggested, allowing for the development of novel therapeutics against this important yet neglected disease. The rise of resistance through the intensive use of drugs targeted to treat specific infectious diseases means that new therapeutics are continually required. Diseases common in the tropics and sub-tropics, classified as neglected tropical diseases, suffer from a lack of new drug treatments due to the difficulty in developing new drugs and the lack of market incentive. One such disease is schistosomiasis, a major human helminth disease caused by worms from the genus Schistosoma. It is currently treated by a 40-year old drug, praziquantel, but its widespread use has led to signs of drug-resistance emerging, with no alternative effective treatments available. To meet this challenge, we have developed an innovative computational drug repurposing pipeline supported by experimental phenotypic screening. Protein kinases emerged from our pipeline as interesting new biological targets. Given that many human kinase inhibitors have been successfully applied specially in cancer therapy and kinases have conserved structures and functions, we also undertook a detailed analysis of the kinases present in all infective Schistosoma species and human host. This allowed identification of new Schistosoma-specific kinase targets and suggest approved drugs to be used for treating schistosomiasis as well as opening new avenues to treat this neglected disease.