Large Library Docking for Polypharmacology

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.