{
  "abstract": "Glycogen synthase kinase-3β (GSK-3β), a central regulator of tau phosphorylation and amyloid pathology, with its β isoform (GSK-3β) used as a main driver of the Alzheimer’s disease (AD) neurodegeneration. It is a validated therapeutic target in AD, yet no isoform-selective, brain penetrant inhibitors have reached clinical use. This paper screens 1000+ FDA-approved drugs by dual-isoform docking (GSK3α/β) and 8-seed redocking, prioritizing compounds by its α/β selectivity (G_select = G_GSK3A − G_GSK3B), CNS penetration, Hinge H-bonds, and pose plausibility. High selectivity alone provided misleading: filgotinib showed the largest G_select (+1.25 ± 0.03 kcal/mol), yet a reproducibly implausible pose, while abemaciclib (ΔG_select = +0.80 ± 0.09 kcal/mol; plausible‑pose fraction = 0.88) and peficitinib (+0.008 ± 0.02 kcal/mol; 1.00) provided a moderate selectivity with structurally reliable binding. Multi-seed redocking led to a hidden instability (loratinib plausible in only 25% of the seeds). This work provides a ranked, hypothesis-generating shortlist by establishing that isoform-selective GSK3β inhibitor discovery demands joint optimization of selectivity, and multi-seed pose stability, rather than affinity of GSK-3β alone. The following results are computationally prioritized candidates, rather than experimentally verified GSK-3β inhibitors.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": null,
  "author_total": 2,
  "authors": [
    {
      "name": "Naranbileg Baljinnyam"
    },
    {
      "name": "Ariuntuguldur Khurelbaatar"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/ah8k65e3r9dab.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010468/v1",
  "fulltext_url": null,
  "id": "ah8k65e3r9dab",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010468/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7221824711",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010468/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-14",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/ah8k65e3r9dab.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:24Z",
      "native_id": "10.26434/chemrxiv.15010468",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010468/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "source:chemrxiv",
      "subfield": "general"
    }
  ],
  "title": "Old Drugs, New Targets: Multi-parameter computational prioritization of FDA‑approved, brain‑penetrant drugs as isoform‑selective GSK‑3β inhibitors for Alzheimer’s disease",
  "title_text": "Old Drugs, New Targets: Multi-parameter computational prioritization of FDA‑approved, brain‑penetrant drugs as isoform‑selective GSK‑3β inhibitors for Alzheimer’s disease",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:24Z",
  "url": "https://research.draconitic.com/paper/ah8k65e3r9dab",
  "venue": "ChemRxiv",
  "versions": []
}