Large Library Docking for Polypharmacology
Wu Y, Vigneron S, Braz J, Srinivasan K, Fink EA, Huang XP, Xu X, Hübner H, Kim JY, Wang J, Pfeiffer T, Sakamoto K, Radchenko DS, Rodriguiz RM, Moroz YS, Irwin JJ, Gmeiner P, Billesboelle C, Roth BL, Basbaum AI, Manglik A, Wetsel WC, Shoichet BK (2026)
Publication Type: Journal article
Publication year: 2026
Journal
Book Volume: 69
Pages Range: 6210-6229
Journal Issue: 5
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.
Authors with CRIS profile
Harald Hübner
Lehrstuhl für Pharmazeutische Chemie
Tara Pfeiffer
Lehrstuhl für Pharmazeutische Chemie
Involved external institutions
University of California San Francisco (UCSF)
United States (USA) (US)
University of North Carolina at Chapel Hill
United States (USA) (US)
Enamine Ltd.
Ukraine (UA)
Duke University Medical Center
United States (USA) (US)
United States (USA) (US)
University of North Carolina at Chapel Hill
United States (USA) (US)
Enamine Ltd.
Ukraine (UA)
Duke University Medical Center
United States (USA) (US)
How to cite
APA:
Wu, Y., Vigneron, S., Braz, J., Srinivasan, K., Fink, E.A., Huang, X.P.,... Shoichet, B.K. (2026). Large Library Docking for Polypharmacology. Journal of Medicinal Chemistry, 69(5), 6210-6229. https://doi.org/10.1021/acs.jmedchem.5c03810
MLA:
Wu, Yujin, et al. "Large Library Docking for Polypharmacology." Journal of Medicinal Chemistry 69.5 (2026): 6210-6229.
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