Abstract
Background: Schistosomiasis is a parasitic protozoal disease caused by flatworms of the genus Schistosoma. Although the disease threatens millions of lives, it is still at the top list of neglected tropical diseases and praziquantel, the only common schistosocidal drug in use, has records of decreasing efficiency and cases of resistance. Also, reports revealed that people in the rural areas, who are most affected, rely mostly on traditional herbal medicines because of limited access to modern healthcare. The use of computers in drug development has become a routine practice because they are cost and time effective.
Objective: We used computational techniques to discover potent Schistosoma inhibitors of natural product origin. Methods: Computer-based techniques were employed to discover anti-schistosoma lead/hit from plant metabolites isolated from African medicinal plants which have shown activity or are responsible for activity against Schistosomes. The plant metabolites were evaluated for ‘drug-likeness’ and docked toward four selected validated Schistosoma drug targets; Glutathione S-transferase, Thioredoxin glutathione reductase, Histone deacetylase and Schistosoma masoni arginase, with PDB codes: 1M9A, 2X99, 4BZ8 and 4Q3T respectively. Results: A total of 27 bioactive compounds with anti-Schistosoma history were retrieved from literature. The phytochemicals with Lipinski violation of ≤ 2 were found to exhibit comparable binding affinities toward the studied targets as the co-crystallized inhibitors. Predicted binding modes of the compounds toward respective target showed key intermolecular interactions involved in the ligandtarget relationship. Moreover, one of the compounds emerged as the most interesting candidate by both being drug-like and inhibiting the activities of the studied enzyme targets at micro-molar range. Conclusion: Our study identified schistosocidal leads with high bioavailability profile and the exploration of binding modes could lay the foundation for synthetic modification of the plant metabolites for the development of novel anti-schistosoma drug(s) with new mechanism of action.Keywords: Schistosomiasis, docking, molecular dynamics simulation, natural products, virtual screening.
Graphical Abstract
59
6