Metabolic clustering analysis as a strategy for compound selection in the drug discovery pipeline for leishmaniasis

Armitage, E. G. et al. (2018) Metabolic clustering analysis as a strategy for compound selection in the drug discovery pipeline for leishmaniasis. ACS Chemical Biology, 13(5), pp. 1361-1369. (doi: 10.1021/acschembio.8b00204) (PMID:29671577)

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Abstract

A lack of viable hits, increasing resistance, and limited knowledge on mode of action is hindering drug discovery for many diseases. To optimize prioritization and accelerate the discovery process, a strategy to cluster compounds based on more than chemical structure is required. We show the power of metabolomics in comparing effects on metabolism of 28 different candidate treatments for Leishmaniasis (25 from the GSK Leishmania box, two analogues of Leishmania box series, and amphotericin B as a gold standard treatment), tested in the axenic amastigote form of Leishmania donovani. Capillary electrophoresis–mass spectrometry was applied to identify the metabolic profile of Leishmania donovani, and principal components analysis was used to cluster compounds on potential mode of action, offering a medium throughput screening approach in drug selection/prioritization. The comprehensive and sensitive nature of the data has also made detailed effects of each compound obtainable, providing a resource to assist in further mechanistic studies and prioritization of these compounds for the development of new antileishmanial drugs.

Item Type:Articles
Additional Information:The authors acknowledge funding provided by the Tres Cantos Open Lab Foundation (TCOLF: program code TC132). In addition, the authors at Universidad San Pablo CEU acknowledge Spanish Ministerio de Economia y Competitividad (CTQ2014-55279-R), and M.P.B. is funded by a core grant to the Wellcome Centre for Molecular Parasitology (104111/Z/14/Z).
Keywords:Molecular medicine, biochemistry, general medicine.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Armitage, Dr Emily Grace and Barrett, Professor Michael
Authors: Armitage, E. G., Godzien, J., Peña, I., López-Gonzálvez, Á., Angulo, S., Gradillas, A., Alonso-Herranz, V., Martín, J., Fiandor, J. M., Barrett, M. P., Gabarro, R., and Barbas, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:ACS Chemical Biology
Publisher:American Chemical Society (ACS)
ISSN:1554-8929
ISSN (Online):1554-8937
Published Online:19 April 2018
Copyright Holders:Copyright © 2018 The American Chemical Society
First Published:First published in ACS Chemical Biology 13(5)1361-1369
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
371799The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/Z & AIII - PARASITOLOGY