Structure-Based Identification of Organoruthenium Compounds as Nanomolar Antagonists of Cannabinoid Receptors

Metal complexes exhibit a diverse
range of coordination
geometries,
representing novel privileged scaffolds with convenient click types
of preparation inaccessible for typical carbon-centered organic compounds.
Herein, we explored the opportunity to identify biologically active
organometallic complexes by reverse docking of a rigid, minimum-size
octahedral organoruthenium scaffold against thousands of protein-binding
pockets. Interestingly, cannabinoid receptor type 1 (CB1) was identified
based on the docking scores and the degree of overlap between the
docked organoruthenium scaffold and the hydrophobic scaffold of the
cocrystallized ligand. Further structure-based optimization led to
the discovery of organoruthenium complexes with nanomolar binding
affinities and high selectivity toward CB2. Our work indicates that
octahedral organoruthenium scaffolds may be advantageous for targeting
the large and hydrophobic binding pockets and that the reverse docking
approach may facilitate the discovery of novel privileged scaffolds,
such as organometallic complexes, for exploring chemical space in
lead discovery.