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Using ChEMBL to Complement Schistosome Drug Discovery
,
Avril Coghlan,
Giampaolo Pagliuca,
Josephine E. Forde-Thomas ,
Matthew Berriman ,
Karl F. Hoffmann
Pharmaceutics, Volume: 15, Issue: 5, Start page: 1359
Swansea University Author:
Gilda Padalino
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DOI (Published version): 10.3390/pharmaceutics15051359
Abstract
Schistosomiasis is one of the most important neglected tropical diseases. Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel. The sustainability of this strategy is at substantial risk due to the possibility of praziqua...
| Published in: | Pharmaceutics |
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| ISSN: | 1999-4923 |
| Published: |
MDPI AG
2023
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa64493 |
| Abstract: |
Schistosomiasis is one of the most important neglected tropical diseases. Until an effective vaccine is registered for use, the cornerstone of schistosomiasis control remains chemotherapy with praziquantel. The sustainability of this strategy is at substantial risk due to the possibility of praziquantel insensitive/resistant schistosomes developing. Considerable time and effort could be saved in the schistosome drug discovery pipeline if available functional genomics, bioinformatics, cheminformatics and phenotypic resources are systematically leveraged. Our approach, described here, outlines how schistosome-specific resources/methodologies, coupled to the open-access drug discovery database ChEMBL, can be cooperatively used to accelerate early-stage, schistosome drug discovery efforts. Our process identified seven compounds (fimepinostat, trichostatin A, NVP-BEP800, luminespib, epoxomicin, CGP60474 and staurosporine) with ex vivo anti-schistosomula potencies in the sub-micromolar range. Three of those compounds (epoxomicin, CGP60474 and staurosporine) also demonstrated potent and fast-acting ex vivo effects on adult schistosomes and completely inhibited egg production. ChEMBL toxicity data were also leveraged to provide further support for progressing CGP60474 (as well as luminespib and TAE684) as a novel anti-schistosomal compound. As very few compounds are currently at the advanced stages of the anti-schistosomal pipeline, our approaches highlight a strategy by which new chemical matter can be identified and quickly progressed through preclinical development. |
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| Keywords: |
ChEMBL; schistosomiasis; drug discovery pipeline; schistosomula; adult worm; bioinformatics; cytotoxicity |
| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
This research was funded by the Wellcome Trust, grant number 107475/Z/15/Z. |
| Issue: |
5 |
| Start Page: |
1359 |