Docking Screens for Dual Inhibitors of Disparate Drug Targets for Parkinson’s Disease

Modulation
of multiple biological targets with a single drug can
lead to synergistic therapeutic effects and has been demonstrated
to be essential for efficient treatment of CNS disorders. However,
rational design of compounds that interact with several targets is
very challenging. Here, we demonstrate that structure-based virtual
screening can guide the discovery of multi-target ligands of unrelated
proteins relevant for Parkinson’s disease. A library with 5.4
million molecules was docked to crystal structures of the A2A adenosine receptor (A2AAR) and monoamine oxidase B (MAO-B).
Twenty-four compounds that were among the highest ranked for both
binding sites were evaluated experimentally, resulting in the discovery
of four dual-target ligands. The most potent compound was an A2AAR antagonist with nanomolar affinity (Ki = 19 nM) and inhibited MAO-B with an IC50 of 100 nM. Optimization guided by the predicted binding modes led
to the identification of a second potent dual-target scaffold. The
two discovered scaffolds were shown to counteract 6-hydroxy­dopamine-induced
neurotoxicity in dopaminergic neuronal-like SH-SY5Y cells. Structure-based
screening can hence be used to identify ligands with specific polypharmacological
profiles, providing new avenues for drug development against complex
diseases.