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Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects

Author

Listed:
  • Tia A. Tummino

    (San Francisco
    San Francisco)

  • Christos Iliopoulos-Tsoutsouvas

    (Northeastern University)

  • Joao M. Braz

    (San Francisco)

  • Evan S. O’Brien

    (Stanford University School of Medicine)

  • Reed M. Stein

    (San Francisco
    San Francisco)

  • Veronica Craik

    (San Francisco)

  • Ngan K. Tran

    (Northeastern University)

  • Suthakar Ganapathy

    (Northeastern University)

  • Fangyu Liu

    (San Francisco)

  • Yuki Shiimura

    (Stanford University School of Medicine
    Kurume University)

  • Fei Tong

    (Northeastern University)

  • Thanh C. Ho

    (Northeastern University)

  • Dmytro S. Radchenko

    (Enamine Ltd.)

  • Yurii S. Moroz

    (Enamine Ltd.
    National Taras Shevchenko University of Kyiv
    Chemspace LLC)

  • Sian Rodriguez Rosado

    (San Francisco)

  • Karnika Bhardwaj

    (San Francisco)

  • Jorge Benitez

    (San Francisco)

  • Yongfeng Liu

    (University of North Carolina at Chapel Hill School of Medicine)

  • Herthana Kandasamy

    (Domain Therapeutics North America Inc.)

  • Claire Normand

    (Domain Therapeutics North America Inc.)

  • Meriem Semache

    (Domain Therapeutics North America Inc.)

  • Laurent Sabbagh

    (Domain Therapeutics North America Inc.)

  • Isabella Glenn

    (San Francisco)

  • John J. Irwin

    (San Francisco)

  • Kaavya Krishna Kumar

    (Stanford University School of Medicine)

  • Alexandros Makriyannis

    (Northeastern University
    Northeastern University)

  • Allan I. Basbaum

    (San Francisco)

  • Brian K. Shoichet

    (San Francisco)

Abstract

Virtual library docking can reveal unexpected chemotypes that complement the structures of biological targets. Seeking agonists for the cannabinoid-1 receptor (CB1R), we dock 74 million tangible molecules and prioritize 46 high ranking ones for de novo synthesis and testing. Nine are active by radioligand competition, a 20% hit-rate. Structure-based optimization of one of the most potent of these (Ki = 0.7 µM) leads to ‘1350, a 0.95 nM ligand and a full CB1R agonist of Gi/o signaling. A cryo-EM structure of ‘1350 in complex with CB1R-Gi1 confirms its predicted docked pose. The lead agonist is strongly analgesic in male mice, with a 2-20-fold therapeutic window over hypolocomotion, sedation, and catalepsy and no observable conditioned place preference. These findings suggest that unique cannabinoid chemotypes may disentangle characteristic cannabinoid side-effects from analgesia, supporting the further development of cannabinoids as pain therapeutics.

Suggested Citation

  • Tia A. Tummino & Christos Iliopoulos-Tsoutsouvas & Joao M. Braz & Evan S. O’Brien & Reed M. Stein & Veronica Craik & Ngan K. Tran & Suthakar Ganapathy & Fangyu Liu & Yuki Shiimura & Fei Tong & Thanh C, 2025. "Virtual library docking for cannabinoid-1 receptor agonists with reduced side effects," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57136-7
    DOI: 10.1038/s41467-025-57136-7
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