{
  "abstract": "Background: More than 90% of rare diseases lack an approved therapy, partly reflecting economic barriers in developing treatments for small patient populations. A common bottleneck is costly and resource-intensive hit-to-lead prioritization. Congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD) is an ultra-rare neurodevelopmental disease often caused by de novo gain-of-function variants in the sodium leak channel NALCN, with no approved treatments. Methods: We developed a cost and resource-efficient, AI-enabled translational drug discovery framework integrating phenotypic high-throughput screening (HTS), structural biology foundation models for hit-to-lead prioritization, and orthogonal experimental validation. We applied this framework for drug repurposing to identify NALCN inhibitors as therapeutic candidates for CLIFAHDD. We screened ~1,200 approved drugs using a fluorescence-based membrane potential assay in doxycycline-inducible HEK293 cells stably expressing the NALCN channelosome. Boltz-2 modeling predicted binding affinity and mode to prioritize hits. Lead repurposing candidates were selected by a multidisciplinary expert review panel. Lead candidates were evaluated using patch-clamp electrophysiology in HEK293 cells expressing wild-type or CLIFAHDD-associated NALCN variants, primary mouse hippocampal neurons, and a C. elegans NALCN gain-of-function model. Results: HTS identified 11 candidate NALCN inhibitors. Boltz-2 prioritized candidates based on predicted binding affinity and predicted binding within the NALCN pore, consistent with a direct pore-blocking mechanism. Aprepitant emerged as the lead candidate after multidisciplinary evaluation based on its predicted mechanism, pharmacologic properties, blood-brain barrier penetration, established safety profile, and regulatory approval in children and adults. Patch-clamp electrophysiology confirmed partial inhibition of NALCN-mediated sodium leak currents in HEK293 cells (IC50;=2.22 μM), with comparable potency against Cav3.1 (IC50=1.63 μM). In primary mouse hippocampal neurons, aprepitant reduced sodium leak currents, hyperpolarized resting membrane potential, and decreased spontaneous firing. Aprepitant rescued hyperlocomotor and dystonic phenotypes in a C. elegans gain-of-function NALCN model. There was notable concordance between AI-predicted hits, phenotypic screening hits, and experimental validation. Conclusion: These findings identify aprepitant as a lead therapeutic candidate for CLIFAHDD, and establish an AI-enabled translational drug discovery framework integrating phenotypic screening, structural modeling, and experimental validation for NALCN channelopathies. This scalable and resource-conscious strategy may accelerate hit-to-lead prioritization and drug discovery for rare and ultra-rare diseases lacking effective therapies.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "name": "Nattaya Thongsepee"
    },
    {
      "name": "Jeremy A Tanner"
    },
    {
      "name": "Srikanth Polusani"
    },
    {
      "name": "Alexandra Typou"
    },
    {
      "name": "Nicholas A Clanton"
    },
    {
      "name": "Brandon B Holmes"
    },
    {
      "name": "Philippe Lory"
    },
    {
      "name": "Donard S Dwyer"
    },
    {
      "name": "Daohong Zhou"
    },
    {
      "name": "Arnaud Monteil"
    },
    {
      "name": "Yaxia Yuan"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/99expkm39x0an.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.08.757476",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.08.757476v1.full",
  "id": "99expkm39x0an",
  "issns": [],
  "landing_url": "https://hal.science/hal-05793804v1",
  "language": "en",
  "licence": "CC-BY-NC-ND-4.0",
  "licence_label": "CC BY-NC-ND 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "neuroscience"
    ],
    [
      "hal",
      "0.scco"
    ],
    [
      "hal",
      "0.sdv"
    ],
    [
      "hal",
      "1.scco.neur"
    ],
    [
      "hal",
      "1.sdv.sp"
    ],
    [
      "hal",
      "2.sdv.sp.pharma"
    ],
    [
      "openalex",
      "1312|Ion channel regulation and function"
    ]
  ],
  "openalex": "W7221084059",
  "pdf_url": "https://hal.science/hal-05793804/document",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-08",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/99expkm39x0an.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:54Z",
      "native_id": "hal-05793804",
      "source": "hal",
      "url": "https://hal.science/hal-05793804v1"
    },
    {
      "first_seen": "2026-10-30T12:26:45Z",
      "native_id": "10.64898/2026.10.08.757476",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.08.757476v1"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "biorxiv:neuroscience",
      "subfield": "neuroscience"
    },
    {
      "field": "medicine",
      "origin": "hal:1.sdv.sp",
      "subfield": "pharmacology-toxicology"
    }
  ],
  "title": "An AI-Enabled Translational Drug Discovery Framework for NALCN Channelopathy: From High-Throughput Screening to Therapeutic Candidate",
  "title_text": "An AI-Enabled Translational Drug Discovery Framework for NALCN Channelopathy: From High-Throughput Screening to Therapeutic Candidate",
  "type": "preprint",
  "updated_at": "2026-10-30T12:26:45Z",
  "url": "https://research.draconitic.com/paper/99expkm39x0an",
  "venue": "HAL",
  "versions": []
}