Using ChEMBL to complement schistosome drug discovery

Padalino, G., Coghlan, A., Pagliuca, G., Forde-Thomas, J. E., Berriman, M. and Hoffmann, K. F. (2023) Using ChEMBL to complement schistosome drug discovery. Pharmaceutics, 15(5), 1359. (doi: 10.3390/pharmaceutics15051359) (PMID:37242601) (PMCID:PMC10220823)

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.

• Item Type: Articles
• Additional Information: This research was funded by the Wellcome Trust, grant number 107475/Z/15/Z.
• Keywords: ChEMBL, schistosomiasis, drug discovery pipeline, schistosomula, adult worm, bioinformatics, cytotoxicity.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Berriman, Professor Matt
• Authors: Padalino, G., Coghlan, A., Pagliuca, G., Forde-Thomas, J. E., Berriman, M., and Hoffmann, K. F.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Pharmaceutics
• Publisher: MDPI
• ISSN: 1999-4923
• ISSN (Online): 1999-4923
• Published Online: 28 April 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Pharmaceutics 15(5): 1359
• Publisher Policy: Reproduced under a Creative Commons License