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TitleLarge Library Docking for Polypharmacology.
Journal, issue, pagesJ Med Chem, Year 2026
Publish dateFeb 19, 2026
AuthorsYujin Wu / Seth Vigneron / Joao Braz / Karthik Srinivasan / Elissa A Fink / Xi-Ping Huang / Xinyu Xu / Harald Huebner / Joseph Y Kim / Jing Wang / Tara Pfeiffer / Kensuke Sakamoto / Dmytro S Radchenko / Ramona M Rodriguiz / Yurii S Moroz / John J Irwin / Peter Gmeiner / Christian Billesboelle / Bryan L Roth / Allan I Basbaum / Aashish Manglik / William C Wetsel / Brian K Shoichet /
PubMed AbstractPolypharmacological 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 ...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 (α/SERT, MOR/SERT, and α/MOR), we sought analgesic compounds. Both the α/SERT and SERT/MOR campaigns led to dual binders with low μM to high nM activities with high hit rates; tetrahydropyridines from the α/SERT campaign were also active against 5-HT. However, even though cryo-EM structures confirmed the docking-predicted poses, optimization struggled to improve potency. Still, in mouse behavioral assays, the most potent α/SERT compound (') 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-HT activities. This study reveals both advantages and challenges of docking for polypharmacology.
External linksJ Med Chem / PubMed:41712624
MethodsEM (single particle)
Resolution3.29 - 3.4 Å
Structure data

71770

9pns

EMDB-71770, PDB-9pns:
Structure of human serotonin transporter bound to small molecule zPZd in lipid nanodisc and NaCl
Method: EM (single particle) / Resolution: 3.4 Å

71775

9ppq

EMDB-71775: Locally-refined Mu-Opioid Receptor bound with novel compound 0505
PDB-9ppq: Locally-refined Mu-Opioid Receptor bound with novel compound 0505 (3-[({[(1P)-1-(3-chlorophenyl)-1H-pyrazol-3-yl]methyl}amino)methyl]phenol)
Method: EM (single particle) / Resolution: 3.34 Å

71783

9pqd

EMDB-71783, PDB-9pqd:
Locally-refined structure of alpha2a adrenergic receptor in complex with Go heterotrimer, scFv16, and compound Z7149
Method: EM (single particle) / Resolution: 3.29 Å

Chemicals

ChemComp-CL:
Unknown entry

PDB-1ciz:
X-RAY STRUCTURE OF HUMAN STROMELYSIN CATALYTIC DOMAIN COMPLEXES WITH NON-PEPTIDE INHIBITORS: IMPLICATION FOR INHIBITOR SELECTIVITY

PDB-1cix:
THREE-DIMENSIONAL STRUCTURE OF ANTIMICROBIAL PEPTIDE TACHYSTATIN A ISOLATED FROM HORSESHOE CRAB

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN/IMMUNE SYSTEM/INHIBITOR / Neurotransmitter Transporter / Inhibitor / Complex / TRANSPORT PROTEIN-IMMUNE SYSTEM-INHIBITOR complex / MEMBRANE PROTEIN / GPCR / Mu-Opioid / Partial Agonist / Active / Drug / Small Molecule / Polypharmacology

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