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Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data

Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. This adverse drug effect can occur in various tissues and is suspected to impact cellular viability. Therefore, it is important to test chemical compounds for t...

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Detalles Bibliográficos
Autores principales: Muehlbacher, Markus, Tripal, Philipp, Roas, Florian, Kornhuber, Johannes
Formato: Online Artículo Texto
Lenguaje:English
Publicado: WILEY-VCH Verlag 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533795/
https://www.ncbi.nlm.nih.gov/pubmed/22945602
http://dx.doi.org/10.1002/cmdc.201200306
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author Muehlbacher, Markus
Tripal, Philipp
Roas, Florian
Kornhuber, Johannes
author_facet Muehlbacher, Markus
Tripal, Philipp
Roas, Florian
Kornhuber, Johannes
author_sort Muehlbacher, Markus
collection PubMed
description Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. This adverse drug effect can occur in various tissues and is suspected to impact cellular viability. Therefore, it is important to test chemical compounds for their potential to induce PLD during the drug design process. PLD has been reported to be a side effect of many commonly used drugs, especially those with cationic amphiphilic properties. To predict drug-induced PLD in silico, we established a high-throughput cell-culture-based method to quantitatively determine the induction of PLD by chemical compounds. Using this assay, we tested 297 drug-like compounds at two different concentrations (2.5 μm and 5.0 μm). We were able to identify 28 previously unknown PLD-inducing agents. Furthermore, our experimental results enabled the development of a binary classification model to predict PLD-inducing agents based on their molecular properties. This random forest prediction system yields a bootstrapped validated accuracy of 86 %. PLD-inducing agents overlap with those that target similar biological processes; a high degree of concordance with PLD-inducing agents was identified for cationic amphiphilic compounds, small molecules that inhibit acid sphingomyelinase, compounds that cross the blood–brain barrier, and compounds that violate Lipinski’s rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD.
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spelling pubmed-35337952013-01-08 Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data Muehlbacher, Markus Tripal, Philipp Roas, Florian Kornhuber, Johannes ChemMedChem Full Papers Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. This adverse drug effect can occur in various tissues and is suspected to impact cellular viability. Therefore, it is important to test chemical compounds for their potential to induce PLD during the drug design process. PLD has been reported to be a side effect of many commonly used drugs, especially those with cationic amphiphilic properties. To predict drug-induced PLD in silico, we established a high-throughput cell-culture-based method to quantitatively determine the induction of PLD by chemical compounds. Using this assay, we tested 297 drug-like compounds at two different concentrations (2.5 μm and 5.0 μm). We were able to identify 28 previously unknown PLD-inducing agents. Furthermore, our experimental results enabled the development of a binary classification model to predict PLD-inducing agents based on their molecular properties. This random forest prediction system yields a bootstrapped validated accuracy of 86 %. PLD-inducing agents overlap with those that target similar biological processes; a high degree of concordance with PLD-inducing agents was identified for cationic amphiphilic compounds, small molecules that inhibit acid sphingomyelinase, compounds that cross the blood–brain barrier, and compounds that violate Lipinski’s rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD. WILEY-VCH Verlag 2012-11 2012-09-03 /pmc/articles/PMC3533795/ /pubmed/22945602 http://dx.doi.org/10.1002/cmdc.201200306 Text en Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
spellingShingle Full Papers
Muehlbacher, Markus
Tripal, Philipp
Roas, Florian
Kornhuber, Johannes
Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data
title Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data
title_full Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data
title_fullStr Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data
title_full_unstemmed Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data
title_short Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data
title_sort identification of drugs inducing phospholipidosis by novel in vitro data
topic Full Papers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533795/
https://www.ncbi.nlm.nih.gov/pubmed/22945602
http://dx.doi.org/10.1002/cmdc.201200306
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