Cargando…

Characterizing ABC-Transporter Substrate-Likeness Using a Clean-Slate Genetic Background

Mutations in ATP Binding Cassette (ABC)-transporter genes can have major effects on the bioavailability and toxicity of the drugs that are ABC-transporter substrates. Consequently, methods to predict if a drug is an ABC-transporter substrate are useful for drug development. Such methods traditionall...

Descripción completa

Detalles Bibliográficos
Autores principales: Sokolov, Artem, Ashenden, Stephanie, Sahin, Nil, Lewis, Richard, Erdem, Nurdan, Ozaltan, Elif, Bender, Andreas, Roth, Frederick P., Cokol, Murat
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494965/
https://www.ncbi.nlm.nih.gov/pubmed/31105571
http://dx.doi.org/10.3389/fphar.2019.00448
_version_ 1783415312114253824
author Sokolov, Artem
Ashenden, Stephanie
Sahin, Nil
Lewis, Richard
Erdem, Nurdan
Ozaltan, Elif
Bender, Andreas
Roth, Frederick P.
Cokol, Murat
author_facet Sokolov, Artem
Ashenden, Stephanie
Sahin, Nil
Lewis, Richard
Erdem, Nurdan
Ozaltan, Elif
Bender, Andreas
Roth, Frederick P.
Cokol, Murat
author_sort Sokolov, Artem
collection PubMed
description Mutations in ATP Binding Cassette (ABC)-transporter genes can have major effects on the bioavailability and toxicity of the drugs that are ABC-transporter substrates. Consequently, methods to predict if a drug is an ABC-transporter substrate are useful for drug development. Such methods traditionally relied on literature curated collections of ABC-transporter dependent membrane transfer assays. Here, we used a single large-scale dataset of 376 drugs with relative efficacy on an engineered yeast strain with all ABC-transporter genes deleted (ABC-16), to explore the relationship between a drug’s chemical structure and ABC-transporter substrate-likeness. We represented a drug’s chemical structure by an array of substructure keys and explored several machine learning methods to predict the drug’s efficacy in an ABC-16 yeast strain. Gradient-Boosted Random Forest models outperformed all other methods with an AUC of 0.723. We prospectively validated the model using new experimental data and found significant agreement with predictions. Our analysis expands the previously reported chemical substructures associated with ABC-transporter substrates and provides an alternative means to investigate ABC-transporter substrate-likeness.
format Online
Article
Text
id pubmed-6494965
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-64949652019-05-17 Characterizing ABC-Transporter Substrate-Likeness Using a Clean-Slate Genetic Background Sokolov, Artem Ashenden, Stephanie Sahin, Nil Lewis, Richard Erdem, Nurdan Ozaltan, Elif Bender, Andreas Roth, Frederick P. Cokol, Murat Front Pharmacol Pharmacology Mutations in ATP Binding Cassette (ABC)-transporter genes can have major effects on the bioavailability and toxicity of the drugs that are ABC-transporter substrates. Consequently, methods to predict if a drug is an ABC-transporter substrate are useful for drug development. Such methods traditionally relied on literature curated collections of ABC-transporter dependent membrane transfer assays. Here, we used a single large-scale dataset of 376 drugs with relative efficacy on an engineered yeast strain with all ABC-transporter genes deleted (ABC-16), to explore the relationship between a drug’s chemical structure and ABC-transporter substrate-likeness. We represented a drug’s chemical structure by an array of substructure keys and explored several machine learning methods to predict the drug’s efficacy in an ABC-16 yeast strain. Gradient-Boosted Random Forest models outperformed all other methods with an AUC of 0.723. We prospectively validated the model using new experimental data and found significant agreement with predictions. Our analysis expands the previously reported chemical substructures associated with ABC-transporter substrates and provides an alternative means to investigate ABC-transporter substrate-likeness. Frontiers Media S.A. 2019-04-25 /pmc/articles/PMC6494965/ /pubmed/31105571 http://dx.doi.org/10.3389/fphar.2019.00448 Text en Copyright © 2019 Sokolov, Ashenden, Sahin, Lewis, Erdem, Ozaltan, Bender, Roth and Cokol. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Pharmacology
Sokolov, Artem
Ashenden, Stephanie
Sahin, Nil
Lewis, Richard
Erdem, Nurdan
Ozaltan, Elif
Bender, Andreas
Roth, Frederick P.
Cokol, Murat
Characterizing ABC-Transporter Substrate-Likeness Using a Clean-Slate Genetic Background
title Characterizing ABC-Transporter Substrate-Likeness Using a Clean-Slate Genetic Background
title_full Characterizing ABC-Transporter Substrate-Likeness Using a Clean-Slate Genetic Background
title_fullStr Characterizing ABC-Transporter Substrate-Likeness Using a Clean-Slate Genetic Background
title_full_unstemmed Characterizing ABC-Transporter Substrate-Likeness Using a Clean-Slate Genetic Background
title_short Characterizing ABC-Transporter Substrate-Likeness Using a Clean-Slate Genetic Background
title_sort characterizing abc-transporter substrate-likeness using a clean-slate genetic background
topic Pharmacology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494965/
https://www.ncbi.nlm.nih.gov/pubmed/31105571
http://dx.doi.org/10.3389/fphar.2019.00448
work_keys_str_mv AT sokolovartem characterizingabctransportersubstratelikenessusingacleanslategeneticbackground
AT ashendenstephanie characterizingabctransportersubstratelikenessusingacleanslategeneticbackground
AT sahinnil characterizingabctransportersubstratelikenessusingacleanslategeneticbackground
AT lewisrichard characterizingabctransportersubstratelikenessusingacleanslategeneticbackground
AT erdemnurdan characterizingabctransportersubstratelikenessusingacleanslategeneticbackground
AT ozaltanelif characterizingabctransportersubstratelikenessusingacleanslategeneticbackground
AT benderandreas characterizingabctransportersubstratelikenessusingacleanslategeneticbackground
AT rothfrederickp characterizingabctransportersubstratelikenessusingacleanslategeneticbackground
AT cokolmurat characterizingabctransportersubstratelikenessusingacleanslategeneticbackground