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Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery

BACKGROUND: Chagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite Trypanosoma cruzi. The current clinical and preclinical pipeline for T. cruzi is extremely sparse and lacks drug target diversity. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we developed a co...

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Autores principales: Ekins, Sean, Lage de Siqueira-Neto, Jair, McCall, Laura-Isobel, Sarker, Malabika, Yadav, Maneesh, Ponder, Elizabeth L., Kallel, E. Adam, Kellar, Danielle, Chen, Steven, Arkin, Michelle, Bunin, Barry A., McKerrow, James H., Talcott, Carolyn
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482694/
https://www.ncbi.nlm.nih.gov/pubmed/26114876
http://dx.doi.org/10.1371/journal.pntd.0003878
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author Ekins, Sean
Lage de Siqueira-Neto, Jair
McCall, Laura-Isobel
Sarker, Malabika
Yadav, Maneesh
Ponder, Elizabeth L.
Kallel, E. Adam
Kellar, Danielle
Chen, Steven
Arkin, Michelle
Bunin, Barry A.
McKerrow, James H.
Talcott, Carolyn
author_facet Ekins, Sean
Lage de Siqueira-Neto, Jair
McCall, Laura-Isobel
Sarker, Malabika
Yadav, Maneesh
Ponder, Elizabeth L.
Kallel, E. Adam
Kellar, Danielle
Chen, Steven
Arkin, Michelle
Bunin, Barry A.
McKerrow, James H.
Talcott, Carolyn
author_sort Ekins, Sean
collection PubMed
description BACKGROUND: Chagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite Trypanosoma cruzi. The current clinical and preclinical pipeline for T. cruzi is extremely sparse and lacks drug target diversity. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we developed a computational approach that utilized data from several public whole-cell, phenotypic high throughput screens that have been completed for T. cruzi by the Broad Institute, including a single screen of over 300,000 molecules in the search for chemical probes as part of the NIH Molecular Libraries program. We have also compiled and curated relevant biological and chemical compound screening data including (i) compounds and biological activity data from the literature, (ii) high throughput screening datasets, and (iii) predicted metabolites of T. cruzi metabolic pathways. This information was used to help us identify compounds and their potential targets. We have constructed a Pathway Genome Data Base for T. cruzi. In addition, we have developed Bayesian machine learning models that were used to virtually screen libraries of compounds. Ninety-seven compounds were selected for in vitro testing, and 11 of these were found to have EC(50) < 10μM. We progressed five compounds to an in vivo mouse efficacy model of Chagas disease and validated that the machine learning model could identify in vitro active compounds not in the training set, as well as known positive controls. The antimalarial pyronaridine possessed 85.2% efficacy in the acute Chagas mouse model. We have also proposed potential targets (for future verification) for this compound based on structural similarity to known compounds with targets in T. cruzi. CONCLUSIONS/ SIGNIFICANCE: We have demonstrated how combining chemoinformatics and bioinformatics for T. cruzi drug discovery can bring interesting in vivo active molecules to light that may have been overlooked. The approach we have taken is broadly applicable to other NTDs.
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spelling pubmed-44826942015-06-29 Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery Ekins, Sean Lage de Siqueira-Neto, Jair McCall, Laura-Isobel Sarker, Malabika Yadav, Maneesh Ponder, Elizabeth L. Kallel, E. Adam Kellar, Danielle Chen, Steven Arkin, Michelle Bunin, Barry A. McKerrow, James H. Talcott, Carolyn PLoS Negl Trop Dis Research Article BACKGROUND: Chagas disease is a neglected tropical disease (NTD) caused by the eukaryotic parasite Trypanosoma cruzi. The current clinical and preclinical pipeline for T. cruzi is extremely sparse and lacks drug target diversity. METHODOLOGY/PRINCIPAL FINDINGS: In the present study we developed a computational approach that utilized data from several public whole-cell, phenotypic high throughput screens that have been completed for T. cruzi by the Broad Institute, including a single screen of over 300,000 molecules in the search for chemical probes as part of the NIH Molecular Libraries program. We have also compiled and curated relevant biological and chemical compound screening data including (i) compounds and biological activity data from the literature, (ii) high throughput screening datasets, and (iii) predicted metabolites of T. cruzi metabolic pathways. This information was used to help us identify compounds and their potential targets. We have constructed a Pathway Genome Data Base for T. cruzi. In addition, we have developed Bayesian machine learning models that were used to virtually screen libraries of compounds. Ninety-seven compounds were selected for in vitro testing, and 11 of these were found to have EC(50) < 10μM. We progressed five compounds to an in vivo mouse efficacy model of Chagas disease and validated that the machine learning model could identify in vitro active compounds not in the training set, as well as known positive controls. The antimalarial pyronaridine possessed 85.2% efficacy in the acute Chagas mouse model. We have also proposed potential targets (for future verification) for this compound based on structural similarity to known compounds with targets in T. cruzi. CONCLUSIONS/ SIGNIFICANCE: We have demonstrated how combining chemoinformatics and bioinformatics for T. cruzi drug discovery can bring interesting in vivo active molecules to light that may have been overlooked. The approach we have taken is broadly applicable to other NTDs. Public Library of Science 2015-06-26 /pmc/articles/PMC4482694/ /pubmed/26114876 http://dx.doi.org/10.1371/journal.pntd.0003878 Text en © 2015 Ekins et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Ekins, Sean
Lage de Siqueira-Neto, Jair
McCall, Laura-Isobel
Sarker, Malabika
Yadav, Maneesh
Ponder, Elizabeth L.
Kallel, E. Adam
Kellar, Danielle
Chen, Steven
Arkin, Michelle
Bunin, Barry A.
McKerrow, James H.
Talcott, Carolyn
Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery
title Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery
title_full Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery
title_fullStr Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery
title_full_unstemmed Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery
title_short Machine Learning Models and Pathway Genome Data Base for Trypanosoma cruzi Drug Discovery
title_sort machine learning models and pathway genome data base for trypanosoma cruzi drug discovery
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4482694/
https://www.ncbi.nlm.nih.gov/pubmed/26114876
http://dx.doi.org/10.1371/journal.pntd.0003878
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