{
  "abstract": "Introduction: Phenotypic screening enables discovery of small molecules without requiring predefined targets, but mechanistic interpretation remains challenging due to polypharmacology and pathway complexity.\n\nMethods: We developed SCOPE (Screening Compound Ontology for Pathway Enrichment), a KNIME-based computational framework that links compound-level screening data to annotated targets and pathways to facilitate generation of mechanistic hypotheses. SCOPE integrates multi-source target annotations and performs sequential target- and pathway-level statistical enrichment using the screened compound library as the background to prioritize shared mechanisms of action.\n\nResults: Applied to a previously established high-throughput screen for modulators of endoplasmic reticulum (ER)-stress induced secretion of ER resident proteins, a process known as exodosis, SCOPE identified calcium signaling as the most enriched KEGG pathway without prior biological context. Its target enrichment revealed several G protein-coupled receptors (GPCRs) linked to inositol 1,4,5-trisphosphate receptors (IP3Rs)-mediated calcium signaling, with widespread antagonism of these receptors among compounds that reduced exodosis, implicating this pathway in the regulation of exodosis. Notably, SCOPE uncovered a novel role for the histamine receptor HRH1 in exodosis, which was validated by RNAi knockdown, gene knockout, and pharmacological modulation, implicating HRH1 as a potential therapeutic target for modulating exodosis.\n\nDiscussion: These results highlight SCOPE’s potential to prioritize experimentally testable targets and pathways from phenotypic screening data.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health",
    "Cellular Stress and Inflammation Section, National Institute on Drug Abuse, National Institutes of Health"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Abhijeet Kapoor"
    },
    {
      "affs": [
        0
      ],
      "name": "Keith J. Kelleher"
    },
    {
      "affs": [
        1
      ],
      "name": "Suzanne M. Underhill"
    },
    {
      "affs": [
        0
      ],
      "name": "Sankalp Jain"
    },
    {
      "affs": [
        0
      ],
      "name": "Darian Williams"
    },
    {
      "affs": [
        1
      ],
      "name": "Brandon K. Harvey"
    },
    {
      "affs": [
        0
      ],
      "name": "Mark J. Henderson"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0wctqmt4c0zsg.bib",
  "cited_by": 0,
  "doi": "10.3389/fphar.2026.1972662",
  "fulltext_url": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13724830/?tool=EBI",
  "id": "0wctqmt4c0zsg",
  "issns": [
    "1663-9812"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1972662/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Research"
    ],
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7222961794",
  "pdf_url": "https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2026.1972662/pdf",
  "pmcid": "PMC13724830",
  "pmid": "42973959",
  "published": "2026-10-19",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/0wctqmt4c0zsg.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:06Z",
      "native_id": "10.3389/fphar.2026.1972662",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fphar.2026.1972662/full"
    },
    {
      "first_seen": "2026-11-03T15:20:51Z",
      "native_id": "PMC:PMC13724830",
      "source": "europepmc",
      "url": "https://europepmc.org/article/PMC/PMC13724830"
    },
    {
      "first_seen": "2026-11-04T12:23:20Z",
      "native_id": "PMC13724830",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fphar.2026.1972662"
    },
    {
      "first_seen": "2026-11-04T15:20:48Z",
      "native_id": "MED:42973959",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42973959"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "issn:1663-9812",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "SCOPE-based target and pathway enrichment identifies the histamine H1 receptor as a regulator of exodosis",
  "title_text": "SCOPE-based target and pathway enrichment identifies the histamine H1 receptor as a regulator of exodosis",
  "type": "peer-reviewed",
  "updated_at": "2026-11-06T12:21:13Z",
  "url": "https://research.draconitic.com/paper/0wctqmt4c0zsg",
  "venue": "Frontiers in Pharmacology",
  "versions": []
}