Sometimes functionally-related proteins recognize similar small molecules. To explore these as targets for polypharmacology, we used functional genomic networks to prioritize proteins linked by the Similarity Ensemble Approach (SEA) method. We focused on sequence dissimilar proteins pairs not previously known to share even a single ligand. On testing, we found eight pairs of proteins where a newly predicted ligand modulated the activity of both proteins, binding in the 5 nM to 13 μM range. We further investigated in depth targeting a pair of proteins involved in synaptic dopamine release. Such functionally relevant bridging ligands may be broadly sought by this approach.

From chemical similarity to rational polypharmacology

253rd National Meeting (2017)

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