A machine learning and live-cell imaging tool kit uncovers small molecules induced phospholipidosis
Copyright © 2023 Elsevier Ltd. All rights reserved..
Drug-induced phospholipidosis (DIPL), characterized by excessive accumulation of phospholipids in lysosomes, can lead to clinical adverse effects. It may also alter phenotypic responses in functional studies using chemical probes. Therefore, robust methods are needed to predict and quantify phospholipidosis (PL) early in drug discovery and in chemical probe characterization. Here, we present a versatile high-content live-cell imaging approach, which was used to evaluate a chemogenomic and a lysosomal modulation library. We trained and evaluated several machine learning models using the most comprehensive set of publicly available compounds and interpreted the best model using SHapley Additive exPlanations (SHAP). Analysis of high-quality chemical probes extracted from the Chemical Probes Portal using our algorithm revealed that closely related molecules, such as chemical probes and their matched negative controls can differ in their ability to induce PL, highlighting the importance of identifying PL for robust target validation in chemical biology.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:30 |
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| Enthalten in: |
Cell chemical biology - 30(2023), 12 vom: 21. Dez., Seite 1634-1651.e6 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hu, Huabin [VerfasserIn] |
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| Links: |
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| Themen: |
Chemical probes |
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| Anmerkungen: |
Date Completed 25.12.2023 Date Revised 12.02.2024 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.chembiol.2023.09.003 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a Drug-induced phospholipidosis (DIPL), characterized by excessive accumulation of phospholipids in lysosomes, can lead to clinical adverse effects. It may also alter phenotypic responses in functional studies using chemical probes. Therefore, robust methods are needed to predict and quantify phospholipidosis (PL) early in drug discovery and in chemical probe characterization. Here, we present a versatile high-content live-cell imaging approach, which was used to evaluate a chemogenomic and a lysosomal modulation library. We trained and evaluated several machine learning models using the most comprehensive set of publicly available compounds and interpreted the best model using SHapley Additive exPlanations (SHAP). Analysis of high-quality chemical probes extracted from the Chemical Probes Portal using our algorithm revealed that closely related molecules, such as chemical probes and their matched negative controls can differ in their ability to induce PL, highlighting the importance of identifying PL for robust target validation in chemical biology | ||
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| 700 | 1 | |a Antolin, Albert A |e verfasserin |4 aut | |
| 700 | 1 | |a Müller, Susanne |e verfasserin |4 aut | |
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