2. Academic Validation
  3. Large Library Docking for Polypharmacology

Large Library Docking for Polypharmacology

  • J Med Chem. 2026 Mar 12;69(5):6210-6229. doi: 10.1021/acs.jmedchem.5c03810.
Yujin Wu 1,  Seth Vigneron 1,  Joao Braz 2,  Karthik Srinivasan 1,  Elissa A Fink 1,  Xi-Ping Huang 3,  Xinyu Xu 1,  Harald Huebner 4,  Joseph Y Kim 1,  Jing Wang 3,  Tara Pfeiffer 4,  Kensuke Sakamoto 3,  Dmytro S Radchenko 5,  Ramona M Rodriguiz 6,  Yurii S Moroz 5 7 8,  John J Irwin 1,  Peter Gmeiner 4,  Christian Billesboelle 1,  Bryan L Roth 3,  Allan I Basbaum 2,  Aashish Manglik 9,  William C Wetsel 6,  Brian K Shoichet 1
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Chemistry, University of California, San Francisco, 1700 fourth St., Byers Hall Suite 508D, San Francisco, California 94158, United States.
  • 2 Department of Anatomy, University of California, San Francisco, San Francisco, California 94158, United States.
  • 3 Department of Pharmacology, University of North Carolina at Chapel Hill, 120 Mason Farm Road, Chapel Hill, North Carolina 27599-7365, United States.
  • 4 Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen 91058, Germany.
  • 5 Enamine Ltd., Kyiv 02094, Ukraine.
  • 6 Departments of Psychiatry and Behavioral Sciences, Neurobiology, and Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, United States.
  • 7 National Taras Shevchenko University of Kyiv, Kyiv 01601, Ukraine.
  • 8 Chemspace LLC, Kyiv 02094, Ukraine.
  • 9 Department of Anesthesia and Perioperative Care, University of California, San Francisco, San Francisco, California 94158, United States.
PMID: 41712624 DOI: 10.1021/acs.jmedchem.5c03810
Abstract

Polypharmacological molecules are attractive for complex illnesses. Here, we explored large library docking for joint activity against target pairs. Retrospectively, as libraries grew, so too did the number of likely dual-activity molecules. In prospective docking of a 900-million molecule library against three target pairs (α2A/SERT, MOR/SERT, and α2A/MOR), we sought analgesic compounds. Both the α2A/SERT and SERT/MOR campaigns led to dual Binders with low μM to high nM activities with high hit rates; tetrahydropyridines from the α2A/SERT campaign were also active against 5-HT2A. However, even though cryo-EM structures confirmed the docking-predicted poses, optimization struggled to improve potency. Still, in mouse behavioral assays, the most potent α2A/SERT compound ('z7149) was effective against pain without inducing conditioned place preference, and the molecule had potent antidepression and anxiolytic drug-like behavior, consistent with its SERT/5-HT2A activities. This study reveals both advantages and challenges of docking for polypharmacology.

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