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Download fileDocking Finds GPCR Ligands in Dark Chemical Matter
dataset
posted on 13.01.2020, 13:08 authored by Flavio Ballante, Axel Rudling, Alexey Zeifman, Andreas Luttens, Duy Duc Vo, John J. Irwin, Jan Kihlberg, Jose Brea, Maria Isabel Loza, Jens CarlssonHigh-throughput
screening has revealed dark chemical matter, a
set of drug-like compounds that has never shown bioactivity despite
being extensively assayed. If dark molecules are found active at a
therapeutic target, their extraordinary selectivity profiles make
excellent starting points for drug development. We explored if ligands
of therapeutically relevant G-protein-coupled receptors could be discovered
by structure-based virtual screening of the dark chemical matter.
Molecular docking screens against crystal structures of the A2A adenosine and the D4 dopamine receptors were
carried out, and 53 top-ranked molecules were evaluated experimentally.
Two ligands of each receptor were discovered, and the most potent
had sub-micromolar affinities. Analysis of bioactivity data showed
that the ligands lacked activity at hundreds of off-targets, including
several that are associated with adverse effects. Our results demonstrate
that virtual screening provides an efficient means to mine the dark
chemical space, which could contribute to development of drugs with
improved safety profiles.