[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-detail-127032-en":3,"doc-seo-127032-105":30,"detail-sidebar-cat-0-en-105":91},{"code":4,"msg":5,"data":6},0,"success",{"doc_id":7,"user_id":8,"nickname":9,"user_avatar":10,"doc_module":4,"category_id":11,"category_name":12,"doc_title":13,"doc_description":14,"doc_content":15,"file_id":16,"file_url":17,"file_type":18,"file_size":19,"view_count":4,"is_deleted":4,"is_public":20,"is_downloadable":20,"audit_status":20,"page_count":21,"language":22,"language_code":23,"site_id":24,"html_lang":23,"table_of_contents":25,"faqs":26,"seo_title":27,"seo_description":14,"update_tm":28,"read_time":29},127032,962084928904,"Asher","https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d",8,"Research & Report","Identification of lysosomotropism using explainable machine learning and morphological profiling cell painting data - Research article","Lysosomotropism describes how certain drug-like compounds preferentially accumulate in lysosomes, a property driven by physicochemical traits yet not reliably predicted by lipophilicity and basicity alone. Using cell painting assay (CPA) morphological profiling as a surrogate, the study identifies that only a minority of compounds within the expected PhysChem window exhibit the lysosomotropic phenotype. Explainable machine learning highlights which properties most contribute to lysosomotropism within this subset.","Open Access Art 2024. Down on 1/9/2025icle . Published on 24 May loaded 10:45:42 AM .  \nhicle is licensed under a Creative C mmons A 3 0 U d[ttr .](ttr .)ibution npor e nce.  \nRSC  \nMedicinal Chemistry  \n|  |  |  |  |  |\n| --- | --- | --- | --- | --- |\n|  | RESEARCH ARTICLE View Article Online |  |  |  |\n|  |  | View Journal | View Issue |  |  |\n\nCite this: RSC Med. Chem., 2024, 15, 2677  \nReceived 12th February 2024, Accepted 9th May 2024  \nDOI: 10.1039/d4md00107a[rsc.li/medchem](rsc.li/medchem)  \nIdentification of lysosomotropism using explainable machine learning and morphological profiling cell painting data†  \nAishvarya Tandon,  a Anna Santura, b Herbert Waldmann,  *a Axel Pahl  *a and Paul Czodrowski  *b  \nLysosomotropism is a phenomenon of diverse pharmaceutical interests because it is a property of compounds with diverse chemical structures and primary targets. While it is primarily reported to becaused by compounds having suitable lipophilicity and basicity values, not all compounds that fulfill such criteria are in fact lysosomotropic. Here, we use morphological profiling by means of the cell painting assay (CPA) as a reliable surrogate to identify lysosomotropism. We noticed that only 35% of the compound subset with matching physicochemical properties show the lysosomotropic phenotype. Based on a matched molecular pair analysis (MMPA), no key substructures driving lysosomotropism could be identified. However, using explainable machine learning (XML), we were able to highlight that higher lipophilicity, basicity, molecular weight, and lower topological polar surface area are among the important properties that induce lysosomotropism in the compounds of this subset.  \n1 Introduction  \nThe lysosome plays a crucial role in the cellular degradation of biopolymers and in processes, such as apoptosis, autophagy, and cell signaling. Lipophilic small molecules and drugs that carry a basic moiety can accumulate in the lysosome, by passing the lysosomal membrane in their neutral form, getting trapped in the compartment due to protonation at the lower pH (Fig. 1) . The pathophysiological consequences of this phenomenon termed lysosomotropism are not yet fully understood, but impairment of lysosomal functionality can be linked to phospholipidosis and disturbed cholesterol homeostasis.1–3  \nRecently lysosomotropism has especially drawn attention in multiple drug repurposing studies targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) . This stems from the crucial involvement of cathepsin L, a lysosomal protease, in cleaving the SARS-CoV-2 spike protein and facilitating virus entry into host cells. By the accumulation oflysosomotropic drugs in the lysosome, the compartment's pH  \na Department of Chemical Biology, Max-Planck-Institute of Molecular Physiology, Otto-Hahn-Str. 11, Dortmund, Germany.  \nE-mail: [herbert.waldmann@mpi-dortmund.mpg.de](herbert.waldmann@mpi-dortmund.mpg.de), [axel.pahl@mpi-dortmund.mpg.de](axel.pahl@mpi-dortmund.mpg.de)  \nb Department of Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany. E-mail: [czodpaul@uni-mainz.de](czodpaul@uni-mainz.de)  \n† Electronic supplementary information (ESI) available. See DOI: [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.1039/d4md00107a](10.1039/d4md00107a)  \nrises, rendering proteolytic enzymes inactive and impeding viral replication.5–7  \nConsequently, well-established lysosomotropic drugs, e.g. chloroquine and hydroxychloroquine, were initially promising drug repurposing candidates against SARS-CoV-2 . However, these drugs failed to demonstrate significant clinical benefits.6,8–13  \nIn a more general sense, lysosomotropism is also a phenomenon of various drugs. It occurs for structurally different compound classes, modes of actions and targets,  \nFig. 1 Lysosomotropism is primarily believed to be driven by lipophilicity and protonation state of the compound. In this diagram,“B” is a lysosomotropic compound and “BH+” is its prot","cbCaiaSOBwtFZ8rB","https://ap.wps.com/l/cbCaiaSOBwtFZ8rB","pdf",2414087,1,15,"English","en",105,"# Introduction\n## Lysosome biology and lysosomotropism mechanism\n## Drug repurposing relevance and SARS-CoV-2 context\n## Reported breadth of lysosomotropic compound classes\n## Prior measurement and prediction approaches\n## Physicochemical window and study rationale","[{\"question\":\"What is lysosomotropism and why is it important in drug discovery?\",\"answer\":\"Lysosomotropism is the tendency of compounds to accumulate in lysosomes, with consequences linked to lysosomal dysfunction. It matters because it affects diverse drug classes and can influence efficacy and safety.\"},{\"question\":\"How does the study use morphological profiling for identifying lysosomotropism?\",\"answer\":\"The work applies the cell painting assay (CPA) to generate morphological profiles and uses these profiles as a surrogate to detect lysosomotropic behavior. It reports that only about 35% of compounds matching the expected physicochemical properties show the phenotype.\"},{\"question\":\"What do explainable machine learning results indicate about key properties?\",\"answer\":\"Explainable machine learning identifies that higher lipophilicity, basicity, molecular weight, and lower topological polar surface area are among the properties that induce lysosomotropism for the examined subset.\"}]","Identification of lysosomotropism using explainable machine learning and morphological profiling cell painting data - Research article | PDF",1785936461,38,{"code":4,"msg":31,"data":32},"ok",{"site_id":24,"language":23,"slug":33,"title":13,"keywords":34,"description":14,"schema_data":35,"social_meta":86,"head_meta":88,"extra_data":90,"updated_unix":28},"identification-of-lysosomotropism-using-explainable-machine-learning-and-morphological-profiling-cell-painting-data-research-article","",{"@graph":36,"@context":85},[37,54,68],{"@type":38,"itemListElement":39},"BreadcrumbList",[40,44,48,51],{"item":41,"name":42,"@type":43,"position":20},"https://docshare.wps.com","Home","ListItem",{"item":45,"name":46,"@type":43,"position":47},"https://docshare.wps.com/document/","Document",2,{"item":49,"name":12,"@type":43,"position":50},"https://docshare.wps.com/document/research-report/",3,{"item":52,"name":13,"@type":43,"position":53},"https://docshare.wps.com/document/identification-of-lysosomotropism-using-explainable-machine-learning-and-morphological-profiling-cell-painting-data-research-article/127032/",4,{"url":52,"name":13,"@type":55,"author":56,"headline":13,"publisher":58,"fileFormat":61,"inLanguage":23,"description":14,"dateModified":62,"datePublished":62,"encodingFormat":61,"isAccessibleForFree":63,"interactionStatistic":64},"DigitalDocument",{"name":9,"@type":57},"Person",{"url":41,"name":59,"@type":60},"DocShare","Organization","application/pdf","2026-08-05",true,{"@type":65,"interactionType":66,"userInteractionCount":4},"InteractionCounter",{"@type":67},"ViewAction",{"@type":69,"mainEntity":70},"FAQPage",[71,77,81],{"name":72,"@type":73,"acceptedAnswer":74},"What is lysosomotropism and why is it important in drug discovery?","Question",{"text":75,"@type":76},"Lysosomotropism is the tendency of compounds to accumulate in lysosomes, with consequences linked to lysosomal dysfunction. It matters because it affects diverse drug classes and can influence efficacy and safety.","Answer",{"name":78,"@type":73,"acceptedAnswer":79},"How does the study use morphological profiling for identifying lysosomotropism?",{"text":80,"@type":76},"The work applies the cell painting assay (CPA) to generate morphological profiles and uses these profiles as a surrogate to detect lysosomotropic behavior. It reports that only about 35% of compounds matching the expected physicochemical properties show the phenotype.",{"name":82,"@type":73,"acceptedAnswer":83},"What do explainable machine learning results indicate about key properties?",{"text":84,"@type":76},"Explainable machine learning identifies that higher lipophilicity, basicity, molecular weight, and lower topological polar surface area are among the properties that induce lysosomotropism for the examined subset.","https://schema.org",{"og:url":52,"og:type":87,"og:title":13,"og:site_name":59,"og:description":14},"article",{"robots":89,"canonical":52},"index,follow",{"doc_id":7,"site_id":24},{"code":4,"msg":5,"data":92},[93,97,101,105,110,115,120,123,128,131,135],{"id":20,"doc_module":4,"doc_module_name":46,"category_name":94,"show_sort_weight":95,"slug":96},"Story & Novel",90,"story-novel",{"id":47,"doc_module":4,"doc_module_name":46,"category_name":98,"show_sort_weight":99,"slug":100},"Literature",80,"literature",{"id":53,"doc_module":4,"doc_module_name":46,"category_name":102,"show_sort_weight":103,"slug":104},"Exam",70,"exam",{"id":106,"doc_module":4,"doc_module_name":46,"category_name":107,"show_sort_weight":108,"slug":109},5,"Comic",60,"comic",{"id":111,"doc_module":4,"doc_module_name":46,"category_name":112,"show_sort_weight":113,"slug":114},6,"Technology",50,"technology",{"id":116,"doc_module":4,"doc_module_name":46,"category_name":117,"show_sort_weight":118,"slug":119},7,"Healthcare",40,"healthcare",{"id":11,"doc_module":4,"doc_module_name":46,"category_name":12,"show_sort_weight":121,"slug":122},30,"research-report",{"id":124,"doc_module":4,"doc_module_name":46,"category_name":125,"show_sort_weight":126,"slug":127},9,"Religion & Spirituality",20,"religion-spirituality",{"id":126,"doc_module":4,"doc_module_name":46,"category_name":129,"show_sort_weight":126,"slug":130},"World Cup","world-cup",{"id":132,"doc_module":4,"doc_module_name":46,"category_name":133,"show_sort_weight":132,"slug":134},10,"Lifestyle","lifestyle",{"id":136,"doc_module":4,"doc_module_name":46,"category_name":137,"show_sort_weight":106,"slug":138},19,"General","general"]