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  3. Large Library Docking For Polypharmacology.
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Large Library Docking for Polypharmacology.

Yujin Wu1, Seth Vigneron1, Joao Braz2

  • 1Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 fourth St., Byers Hall Suite 508D, San Francisco, California 94158, United States.

Journal of Medicinal Chemistry
|February 19, 2026

View abstract on PubMed

Summary
This summary is machine-generated.

Large library docking identified dual-activity molecules for complex diseases. While potent compounds were found for pain, depression, and anxiety, challenges remain in optimizing their efficacy.

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Area of Science:

  • Computational chemistry
  • Pharmacology
  • Drug discovery

Background:

  • Polypharmacology, the simultaneous targeting of multiple biological targets, offers a promising strategy for treating complex diseases.
  • Identifying molecules with joint activity against specific target pairs is crucial for developing effective multi-target therapies.

Purpose of the Study:

  • To explore the utility of large library docking for discovering dual-activity molecules against selected target pairs.
  • To identify potential analgesic compounds through prospective docking against alpha2A/SERT, MOR/SERT, and alpha2A/MOR targets.

Main Methods:

  • Retrospective analysis of library growth and dual-activity molecule identification.
  • Prospective virtual screening of a 900-million molecule library using docking against three target pairs.
  • Confirmation of docking-predicted poses using cryo-electron microscopy (cryo-EM) structures.
  • In vivo evaluation of compound efficacy in mouse behavioral assays.

    • Main Results:

    • Docking campaigns identified dual binders with low μM to high nM activities and high hit rates for alpha2A/SERT and SERT/MOR targets.
    • Tetrahydropyridine compounds from the alpha2A/SERT campaign also exhibited activity against 5-HT2A.
    • Cryo-EM confirmed docking-predicted poses, but subsequent optimization faced challenges in improving potency.
    • The lead alpha2A/SERT compound (z7149) demonstrated efficacy in pain assays without conditioned place preference, and exhibited antidepressant and anxiolytic-like behavior.

    Conclusions:

    • Large library docking is a viable strategy for discovering polypharmacological agents, yielding promising hits for complex conditions.
    • Despite structural validation, optimizing the potency of identified dual-activity molecules presents significant challenges.
    • The study highlights both the potential and limitations of computational docking in advancing polypharmacology for therapeutic benefit.