Using ChEMBL to Complement Schistosome Drug Discovery

Padalino, Gilda; Coghlan, Avril; Pagliuca, Giampaolo; Forde-Thomas, Josephine E.; Berriman, Matthew; Hoffmann, Karl F.

doi:10.3390/pharmaceutics15051359

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Using ChEMBL to Complement Schistosome Drug Discovery

Gilda Padalino

, 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...

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Published in:	Pharmaceutics
ISSN:	1999-4923
Published:	MDPI AG 2023
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URI:	https://cronfa.swan.ac.uk/Record/cronfa64493
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spelling	v2 64493 2023-09-08 Using ChEMBL to Complement Schistosome Drug Discovery 7e5526209f02734f57ba19b0d17604ec 0000-0001-8580-1293 Gilda Padalino Gilda Padalino true false 2023-09-08 PHAR 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. Journal Article Pharmaceutics 15 5 1359 MDPI AG 1999-4923 ChEMBL; schistosomiasis; drug discovery pipeline; schistosomula; adult worm; bioinformatics; cytotoxicity 28 4 2023 2023-04-28 10.3390/pharmaceutics15051359 http://dx.doi.org/10.3390/pharmaceutics15051359 COLLEGE NANME Pharmacy COLLEGE CODE PHAR Swansea University This research was funded by the Wellcome Trust, grant number 107475/Z/15/Z. 2024-01-08T14:13:05.6811311 2023-09-08T15:56:05.8587393 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Pharmacy Gilda Padalino 0000-0001-8580-1293 1 Avril Coghlan 2 Giampaolo Pagliuca 3 Josephine E. Forde-Thomas 0000-0002-7202-3565 4 Matthew Berriman 0000-0002-9581-0377 5 Karl F. Hoffmann 6 64493__28710__0bd622d79e6d462e93a9d9bf1ee697de.pdf 64493.VOR.pdf 2023-10-05T09:30:48.7730596 Output 4917749 application/pdf Version of Record true © 2023 by the authors. Licensee MDPI, Basel, Switzerland. Distributed under the terms of a Creative Commons Attribution 4.0 License (CC BY 4.0). true eng https://creativecommons.org/licenses/by/4.0/
title	Using ChEMBL to Complement Schistosome Drug Discovery
spellingShingle	Using ChEMBL to Complement Schistosome Drug Discovery Gilda Padalino
title_short	Using ChEMBL to Complement Schistosome Drug Discovery
title_full	Using ChEMBL to Complement Schistosome Drug Discovery
title_fullStr	Using ChEMBL to Complement Schistosome Drug Discovery
title_full_unstemmed	Using ChEMBL to Complement Schistosome Drug Discovery
title_sort	Using ChEMBL to Complement Schistosome Drug Discovery
author_id_str_mv	7e5526209f02734f57ba19b0d17604ec
author_id_fullname_str_mv	7e5526209f02734f57ba19b0d17604ec_***_Gilda Padalino
author	Gilda Padalino
author2	Gilda Padalino Avril Coghlan Giampaolo Pagliuca Josephine E. Forde-Thomas Matthew Berriman Karl F. Hoffmann
format	Journal article
container_title	Pharmaceutics
container_volume	15
container_issue	5
container_start_page	1359
publishDate	2023
institution	Swansea University
issn	1999-4923
doi_str_mv	10.3390/pharmaceutics15051359
publisher	MDPI AG
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Pharmacy{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Pharmacy
url	http://dx.doi.org/10.3390/pharmaceutics15051359
document_store_str	1
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description	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.
published_date	2023-04-28T14:13:07Z
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Using ChEMBL to Complement Schistosome Drug Discovery

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