Chemistry: Chemical con artists foil drug discovery : Nature News

 ar·ti·fact  ˈärdəfakt/

something observed in a scientific investigation or experiment that is not naturally present but occurs as a result of the preparative or investigative procedure.  "widespread tissue infection may be a technical artifact"

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Nature News

 Naivety about promiscuous, assay-duping molecules is polluting the literature and wasting resources, warn Jonathan Baell and Michael A. Walters.

Academic researchers, drawn into drug discovery without appropriate guidance, are doing muddled science. When biologists identify a protein that contributes to disease, they hunt for chemical compounds that bind to the protein and affect its activity. A typical assay screens many thousands of chemicals. ‘Hits’ become tools for studying the disease, as well as starting points in the hunt for treatments.

But many hits are artefacts — their activity does not depend on a specific, drug-like interaction between molecule and protein. A true drug inhibits or activates a protein by fitting into a binding site on the protein. Artefacts have subversive reactivity that masquerades as drug-like binding and yields false signals across a variety of assays^{1, 2}.
These molecules — pan-assay interference compounds, or PAINS — have defined structures, covering several classes of compound (see ‘Worst offenders’). But biologists and inexperienced chemists rarely recognize them. Instead, such compounds are reported as having promising activity against a wide variety of proteins. Time and research money are consequently wasted in attempts to optimize the activity of these compounds. Chemists make multiple analogues of apparent hits hoping to improve the ‘fit’ between protein and compound. Meanwhile, true hits with real potential are neglected.

All pain, no gain
Some of the compounds that should ring the most warning bells are toxoflavin and polyhydroxylated natural phytochemicals such as curcumin, EGCG (epigallocatechin gallate), genistein and resveratrol. These, their analogues and similar natural products persist in being followed up as drug leads and used as ‘positive’ controls even though their promiscuous actions are well-documented^{8, 9}....

 Very occasionally, a PAINS compound does interact with a protein in a specific drug-like way. If it does, its structure could be optimized through medicinal chemistry. However, this path is fraught — it can be difficult to distinguish when activity is caused by a drug-like mechanism or something more insidious.