In silico repositioning-chemogenomics strategy identifies new drugs with potential activity against multiple life stages of Schistosoma mansoni

Bruno J Neves, Rodolpho C Braga, José C B Bezerra, Pedro V L Cravo, Carolina H Andrade

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish
Article numbere3435
Number of pages12
JournalPLoS Neglected Tropical Diseases
Volume9
Issue number1
DOIs
Publication statusPublished - Jan 2015

Keywords

  • Animals
  • Computer Simulation
  • Drug Discovery
  • Genome, Helminth
  • Genomics
  • Helminth Proteins
  • Life Cycle Stages
  • Schistosoma mansoni
  • Schistosomiasis mansoni
  • Schistosomicides
  • Journal Article
  • Research Support, Non-U.S. Gov't

UN Sustainable Development Goals (SDGs)

  • SDG 3 - Good Health and Well-Being

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