'Promiscuous' Molecules Are Duping Druggists

Researchers have too many PAINS in their assays

Chemicals in flasks

Photo by Joe Sullivan on Flickr, CC BY 2.0

When researchers are looking to treat a disease, a common method is to find a protein associated with the ailment and find a way to render it useless. Often, scientists will swamp the protein in thousands of chemicals and see what sticks--literally. However, a commentary in Nature warns that scientists are too easily fooled by these tests.

Chemicals that bind to harmful proteins can shut down their activity, and disrupting the activity of a harmful protein is often the first step toward a cure. The problem is, a relatively small group of chemicals appear to disrupt many different and unrelated proteins, but they are actually useless. Or worse, they disrupt healthy processes as well. The authors of the Nature piece say these problematic chemicals (with obscure names like toxoflavin and isothiasolone) and their false positives gum up the works of drug research.

These molecules — pan-assay interference compounds, or PAINS — have defined structures, covering several classes of compound … 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.

The writers end their piece with a call for greater vigilance among chemists and biologists for problematic PAINS.