Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data
| Autor: | Johannes Kornhuber, Markus Muehlbacher, Florian Roas, Philipp Tripal |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
Drug
Drug-Related Side Effects and Adverse Reactions In silico media_common.quotation_subject Pharmacology Biochemistry lysosomal storage disorders Surface-Active Agents Cell Line Tumor Lysosome Drug Discovery medicine Humans Computer Simulation General Pharmacology Toxicology and Pharmaceutics phospholipids media_common cationic amphiphilic drugs Phospholipidosis Chemistry Organic Chemistry phospholipidosis Full Papers Small molecule In vitro Lysosomal Storage Diseases enzymes and coenzymes (carbohydrates) medicine.anatomical_structure Pharmaceutical Preparations Drug Design Lipinski's rule of five Molecular Medicine lipids (amino acids peptides and proteins) Acid sphingomyelinase Lysosomes toxicology medicine.drug |
| Zdroj: | Chemmedchem |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201200306 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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