Distant Polypharmacology among MLP Chemical Probes

Small molecules are essential tool
compounds to probe the role
of proteins in biology and advance toward more efficient therapeutics.
However, they are used without a complete knowledge of their selectivity
across the entire proteome, at risk of confounding their effects due
to unknown off-target interactions. Current state-of-the-art computational
approaches to predicting the affinity profile of small molecules offer
a means to anticipate potential nonobvious selectivity liabilities
of chemical probes. The application of in silico target
profiling on the full set of chemical probes from the NIH Molecular
Libraries Program (MLP) resulted in the identification of biologically
relevant in vitro affinities for proteins distantly
related to the primary targets of ML006, ML123, ML141, and ML204,
helping to lower the risk of their further use in chemical biology.