PAINS ('Pan-Assay Interference Compounds') are rapidly becoming the �irreversible inhibitors� of the second decade of the 21st century. That is, while the wave of fear concerning covalent inhibitors has crested and slowly receded, PAINS and their like appear to be the next tsunami on the horizon of the medicinal chemistry landscape, particularly at the pre-clinical stages of the academic drug discovery process. Three challenges face the world of academic drug discovery: (1) high-throughput screening (virtual or real) has now become the de facto approach for chemical matter discovery; (2) there appears to be a general lack of knowledge regarding PAINS compounds in the medicinal chemistry community; and (3) too little is known about the mechanism(s) of interference by some of these well-disguised bad actors. We will report on our investigations into structure-interference relationships (SIR) that were prompted by our recent riding out of a perfect storm assay. Many of the interference compounds we discovered appeared to have reproducible relative activities that some might interpret as SAR of a more positive nature. Additionally, we will report on a well-trodden series of compounds that interfere by a 'triple threat' of interference mechanisms (including instability in assay buffer, thiol reactivity and redox activity), leading us to question the utility of certain bioactivity results reported in the literature. Finally, we will make a request that researchers carefully consider the �natural histories� of the hits they report and consider rigorous structural prioritization in their project screening trees.

PAINful lessons: Philosophical remarks, structure interference relationships, and compound natural histories

248th National Meeting (2014)

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