PAINS, or pan-assay interference compounds, comprise a subject that has cropped up several times here (and here, and here, and here). Although not exclusive to fragments, I wanted to point out a thorough and insightful analysis by Jonathan Baell over at HTSPAINS in which he traces the lineage of a dubious series through paper after paper all the way back to 2001. The assays, models, and mechanistic theories all change, and the molecules keep getting uglier as they devolve from chalcones to bis-benzylidenepiperidones. It’s an entertaining and educational look at sloppy science. He ends with an important point:
People still don’t realize how easy it is to get a biological readout. The more subversive a compound, the more likely this is.
Indeed, even with decent looking molecules it can be difficult to figure out exactly what is going on; with PAINS you may as well start explaining things in terms of phlogiston and humorism.
I can’t help thinking of the late Efraim Racker’s admonishment: “don’t waste clean thinking on dirty enzymes.” Even when they are chemically pure, PAINS molecules are mechanistically dirty. The amount of effort wasted on them boggles the imagination, so keep them out of your libraries!