Detergent Dependably Busts Up Aggregates In Drug Screens

Chemical library compounds that clump together to form aggregates can plague high-throughput drug screens. And as if that weren’t enough, a study suggests they do so unpredictably (J. Med. Chem., DOI: 10.1021/jm901070c). The work reemphasizes the importance of using detergents to weed out the aggregators, which bind to targets in unproductive ways. Aggregators and other false positives are a drain on drugmakers’ resources, which prompted a team led by Anton Simeonov of the NIH Chemical Genomics Center and Brian K. Shoichet of the University of California, San Francisco, to analyze false positives from a screen for inhibitors of cruzain, a cysteine protease. It’s known that many types of false positives are context dependent, but it remains tempting to simply blacklist even potentially important molecules that are persistent aggregators, the researchers note. Their results suggest that making a permanent list is hard to do because different types of compounds are nearly equally prone to aggregation. However, the team was able to eliminate most spurious hits due to aggregation in its nearly 200,000 compound screen by adding a detergent such as Triton X-100 to prevent clumping.