Research Article: In Silico Repositioning-Chemogenomics Strategy Identifies New Drugs with Potential Activity against Multiple Life Stages of Schistosoma mansoni

Date Published: January 8, 2015

Publisher: Public Library of Science

Author(s): Bruno J. Neves, Rodolpho C. Braga, José C. B. Bezerra, Pedro V. L. Cravo, Carolina H. Andrade, Banchob Sripa.

Abstract: Morbidity and mortality caused by schistosomiasis are serious public health problems in developing countries. Because praziquantel is the only drug in therapeutic use, the risk of drug resistance is a concern. In the search for new schistosomicidal drugs, we performed a target-based chemogenomics screen of a dataset of 2,114 proteins to identify drugs that are approved for clinical use in humans that may be active against multiple life stages of Schistosoma mansoni. Each of these proteins was treated as a potential drug target, and its amino acid sequence was used to interrogate three databases: Therapeutic Target Database (TTD), DrugBank and STITCH. Predicted drug-target interactions were refined using a combination of approaches, including pairwise alignment, conservation state of functional regions and chemical space analysis. To validate our strategy, several drugs previously shown to be active against Schistosoma species were correctly predicted, such as clonazepam, auranofin, nifedipine, and artesunate. We were also able to identify 115 drugs that have not yet been experimentally tested against schistosomes and that require further assessment. Some examples are aprindine, gentamicin, clotrimazole, tetrabenazine, griseofulvin, and cinnarizine. In conclusion, we have developed a systematic and focused computer-aided approach to propose approved drugs that may warrant testing and/or serve as lead compounds for the design of new drugs against schistosomes.

Partial Text: Schistosomiasis is one of the main neglected tropical diseases affecting humans. It is caused by flatworms of the genus Schistosoma (S. mansoni, S. japonicum, S. haematobium, S. intercalatum and S. mekongi) [1]–[3]. This parasitic disease ranks second only after malaria in terms of its public health importance [4] because of its chronic and debilitating characteristics that result in a substantial burden on human health [5], [6]. Recent estimates suggest that more than 249 million people were infected in 78 endemic countries located in sub-Saharan Africa, the Middle East, the Caribbean, and South America, resulting in 200,000 deaths annually [7].

The main goal of this study was to identify drugs approved for clinical use in humans that may have potential schistosomicidal activity by performing a search of publicly available drug/target databases. However, since most target databases are only starting to be established, the predicted S. mansoni targets are not yet scored for druggability. The druggability concept adds a structural dimension and evaluates the likelihood that small drug-like molecules can bind a given target with sufficient potency to alter its activity [68]–[70]. Druggability is related to many factors, including the size of targets, the presence of pockets, and the overall charge and hydrophobicity of the interaction surface [68]. A number of factors were considered in this study in order to provide both confidence for the data generated and a solid basis from which to predict the druggability of individual S. mansoni targets. The predicted S. mansoni targets were considered druggable if they presented a sequence overlap ≥80%, a score ≥0.8, or an E-value ≤10−20 in relation to their predicted homologous targets and the high or moderate conservation of the functional regions. The overlapping sequences and analysis of functional regions among approved drug targets and S. mansoni targets revealed the importance of each position for the function of the predicted protein and the possible preservation of affinity for the predicted drug. Following this precondition, we were able to identify 168 drugs with the potential to inhibit their targets known to be transcribed in multiple life stages of S. mansoni. Moreover, in validation of the proposed chemogenomic strategy, several drugs previously demonstrated to be active against Schistosoma species in experimental assays were predicted by our methodology (Table 1 and S3 Table). Consequently, we were confident that our strategy for predicting schistosomicidal drugs is useful.



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