Structural Basis for the Rational Design of UAMC-1110-Based FAP Radiopharmaceuticals
- 1Forschungszentrum Juelich
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.
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BibTeX
@misc{zhang2026structural,
title = {{Structural Basis for the Rational Design of UAMC-1110-Based FAP Radiopharmaceuticals}},
author = {C. Zhang and J. Gerhards and L. Scharbert and J. Cardinale and F. Giesel and B. Strodel},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.11.758356},
url = {https://www.biorxiv.org/content/10.64898/2026.10.11.758356v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Structural Basis for the Rational Design of UAMC-1110-Based FAP Radiopharmaceuticals
AU - C. Zhang
AU - J. Gerhards
AU - L. Scharbert
AU - J. Cardinale
AU - F. Giesel
AU - B. Strodel
PY - 2026
DA - 2026/10/11
PB - bioRxiv
DO - 10.64898/2026.10.11.758356
UR - https://www.biorxiv.org/content/10.64898/2026.10.11.758356v1
AB - 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.
ER -