To
investigate large library docking’s ability to find molecules
with joint activity against on-targets and selectivity versus antitargets,
the dopamine D<sub>2</sub> and serotonin 5-HT<sub>2A</sub> receptors
were targeted, seeking selectivity against the histamine H<sub>1</sub> receptor. In a second campaign, κ-opioid receptor ligands
were sought with selectivity versus the μ-opioid receptor. While
hit rates ranged from 40% to 63% against the on-targets, they were
just as good against the antitargets, even though the molecules were
selected for their putative lack of binding to the off-targets. Affinities,
too, were often as good or better for the off-targets. Even though
it was occasionally possible to find selective molecules, such as
a mid-nanomolar D<sub>2</sub>/5-HT<sub>2A</sub> ligand with 21-fold
selectivity versus the H<sub>1</sub> receptor, this was the exception.
Whereas false-negatives are tolerable in docking screens against on-targets,
they are intolerable against antitargets; addressing this problem
may demand new strategies in the field