title: In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni.
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.
authors.affiliation: LabMol - Laboratory for Drug Design and Modeling, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Brazil; Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil.
authors.forename: Bruno J
authors.initials: BJ
authors.lastname: Neves
authors.affiliation: LabMol - Laboratory for Drug Design and Modeling, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Brazil; Instituto de Química, Universidade Federal de Goiás, Goiaânia, Brazil.
authors.forename: Rodolpho C
authors.initials: RC
authors.lastname: Braga
authors.affiliation: Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil.
authors.forename: José C B
authors.initials: JC
authors.lastname: Bezerra
authors.affiliation: Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil; Centro de Malária e Doenças Tropicais, Instituto de Higiene e Medicina Tropical, Universidade Nova de Lisboa, Lisboa, Portugal.
authors.forename: Pedro V L
authors.initials: PV
authors.lastname: Cravo
authors.affiliation: LabMol - Laboratory for Drug Design and Modeling, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, Brazil; Instituto de Patologia Tropical e Saúde Pública, Universidade Federal de Goiás, Goiânia, Brazil.
authors.forename: Carolina H
authors.initials: CH
authors.lastname: Andrade
mesh_terms: D000818:Animals; D003198:Computer Simulation; D055808:Drug Discovery; D049751:Genome, Helminth; D023281:Genomics; D015801:Helminth Proteins / Q000378:metabolism; D008018:Life Cycle Stages / Q000187:drug effects; D012550:Schistosoma mansoni / Q000187:drug effects*; D012555:Schistosomiasis mansoni / Q000469:parasitology; D012556:Schistosomicides / Q000494:pharmacology*
chemical_list: D015801:Helminth Proteins; D012556:Schistosomicides