Abstract
Background: Praziquantel, as the only drug for the treatment of schistosomiasis, is under serious threat due to the emergence of resistant strains of Schistosoma species. There is an urgent need to search for alternative chemotherapy to supplement or complement praziquantel. Schistosoma dihydroorotate dehydrogenase (DHODH) has been recommended as a druggable target for schistosomiasis chemotherapy. The development of novel molecular modeling approaches, alongside with computational tools and rapid sequencing of pathogen genomes, have facilitated drug discovery. Therefore, the aim of this study was to employ computational approaches to screen compounds against Schistosoma mansoni DHODH. Methods: In this study, DHODH was used to blast on the latest version of DrugBank that contained 12,110 compounds, resulting in 26 drugs that can bind. Results: In silico docking shows that 13 drugs can bind strongly with an estimated free energy of binding, total intermolecular energy and estimated inhibition constant (Ki) greater than or equal to -8.6 kcal/mol, -8.12 kcal/mol and 1.12 µM, respectively. These compounds include the approved drugs manitimus, capecitabine, brequinar analog and leflunomide. Conclusions: These results indicate that these drugs have the potential for use in the control of schistosomiasis in the future.
Highlights
The public health impacts of schistosomiasis, caused by Schistosoma species, are second only to malaria in endemic regions and it is an important neglected tropical disease (NTD)[1,2]
The results show that 13 approved drugs used in the treatment of other diseases have the potential to inhibit the activities of Schistosoma mansoni dihydroorotate dehydrogenase (SmDHODH)
One Homo sapien dihydroorotate dehydrogenase (HsDHODH) sequence, two Mus musculus dihydroorotate dehydrogenase (MmDHODH) sequences and two Rattus rattus dihydroorotate dehydrogenase (RrDHODH) sequences (Figure 1 and Project 1, Extended data)[51] were included in the study for proper comparison as mammals, including humans, are the hosts, while rats and mice are commonly used in the laboratory for schistosomiasis studies
Summary
The public health impacts of schistosomiasis, caused by Schistosoma species, are second only to malaria in endemic regions and it is an important neglected tropical disease (NTD)[1,2]. More than 240 million people are infected with one or more Schistosoma species in the tropical or subtropical regions[2,3,4]. Results: In silico docking shows that 13 drugs can bind strongly with an estimated free energy of binding, total intermolecular energy and estimated inhibition constant (Ki) greater than or equal to -8.6 kcal/mol, -8.12 kcal/mol and 1.12 μM, respectively. These compounds include the approved drugs manitimus, capecitabine, brequinar analog and leflunomide. Conclusions: These results indicate that these drugs have the potential for use in the control of schistosomiasis in the future
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