Your natural product contains a promiscuous pains motif: Is it useful as a biochemical probe or in drug discovery?

With increasing access to high throughput screening, academic drug discovery is being accompanied by a plethora of publications that report screening hits as good starting points for drug discovery or as useful tool compounds, whereas in many cases this is not so. These compounds may be protein-reactive but can also interfere in bioassays via a number of other means, many of which may remain unknown, and it can be very hard to prove early on that they represent false starts.^{1 – 5} We have termed such compounds Pan-Assay Interference Compounds, or PAINS. Examples of such compound cores are shown below. Some of these cores are prevalent in natural products. PAINS were defined from HTS libraries devoid of natural products. So how should one view PAINS-containing natural products in terms of useful biochemical probes or potential therapeutics? This presentation will delve into such issues.

[1] Baell JB & Holloway GA. New substructure filters for removal of pan assay interference compounds [PAINS] from screening libraries and for their exclusion in bioassays. J. Med. Chem. 53, 2719 – 2740 (2010).

[2] Baell JB. Observations on Screening-Based Research and Some Concerning Trends in the Literature. Future Med. Chem. 2, 1529 – 1546 (2010).

[3] Baell JB. Redox active nuisance screening compounds and their classification. Drug Discov. Today 16, 840 – 841 (2011).

[4] Baell JB, Ferrins L, Falk H, Nikolakopoulos G. PAINS: Relevance to Tool Compound Discovery and Fragment-Based Screening. Aust. J. Chem. 66 (2013) 1483 – 1494.

[5] Baell J & Walters MA. Chemical con artists foil drug discovery. Nature 513 (2014) 481 – 483.