{
  "abstract": "Radioligands targeting fibroblast activation protein alpha (FAP) are promising tools for cancer diagnosis and therapy. However, the molecular binding mode of clinically established UAMC-1110-derived ligands such as FAPI-46 remains insufficiently characterized. To simplify synthesis while preserving key binding properties, we designed two novel derivatives - FAP-DD-101 (short aminoalkyl linker) and FAP-DD-102 (extended aminohexanoic acid spacer) - and evaluated them alongside FAPI-46 using molecular docking and all-atom molecular dynamics (MD) simulations. Across all derivatives, we identified a highly stable, energetically favorable charge-anchored binding mode, in which the 2-cyano-4,4-difluoropyrrolidine head anchors in a negatively charged subregion formed by Glu202, Glu203, and Glu204, mimicking the binding architecture observed in the FAP-linagliptin complex. MD trajectories confirmed that FAPI-46 and FAP-DD-101 maintain exceptional stability in this pose, with several non-anchored FAPI-46 trajectories spontaneously evolving toward engagement with this electrostatic subregion. For FAP-DD-102, linker elongation slightly reduced pose robustness, yet initial charge-anchored states still yielded superior average binding energies and vector stability compared to non-anchored poses. Overall, these findings elucidate the key structural determinants of FAP recognition, establishing a rational framework for designing synthetically accessible FAPI radiotracers with retained binding stability.",
  "abstract_shown": true,
  "affiliations": [
    "Forschungszentrum Juelich"
  ],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "name": "C. Zhang"
    },
    {
      "name": "J. Gerhards"
    },
    {
      "name": "L. Scharbert"
    },
    {
      "name": "J. Cardinale"
    },
    {
      "name": "F. Giesel"
    },
    {
      "affs": [
        0
      ],
      "name": "B. Strodel"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/33q44m23c6d5b.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.11.758356",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.11.758356v1.full",
  "id": "33q44m23c6d5b",
  "issns": [],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.11.758356v1",
  "language": null,
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "biophysics"
    ],
    [
      "openalex",
      "2730|Peptidase Inhibition and Analysis"
    ]
  ],
  "openalex": "W7221538421",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.11.758356v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-11",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/33q44m23c6d5b.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:27:22Z",
      "native_id": "10.64898/2026.10.11.758356",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.11.758356v1"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "biorxiv:biophysics",
      "subfield": "biophysics"
    }
  ],
  "title": "Structural Basis for the Rational Design of UAMC-1110-Based FAP Radiopharmaceuticals",
  "title_text": "Structural Basis for the Rational Design of UAMC-1110-Based FAP Radiopharmaceuticals",
  "type": "preprint",
  "updated_at": "2026-10-30T12:27:22Z",
  "url": "https://research.draconitic.com/paper/33q44m23c6d5b",
  "venue": "bioRxiv",
  "versions": []
}