Over the last decade, there has been an increasing focus on the origins of non-specific screening hits.  In parallel, there have been significant efforts to simplify the post screening hit qualification campaign by prospectively identifying non-specific hits among the set of all screening hits using computational and experimental approaches.  A common theme of this research is that many non-specific hits do not engage targets in one-to-one binding interactions.  Based on these data, we sought to (1) interrogate the assumption that successfully developed and marketed compounds lacked this non-specific binding propensity and (2) evaluate several biophysical and computational approaches to identify compound behaviors and properties that correlate with non-ideal target engagement.  Based on our results, we suggest two rapid assays and a simple computational approach to identify suspect compounds among screening hits.

Biophysical characterization of promiscuous protein binding by marketed drugs

248th National Meeting (2014)

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