Gaining confidence in high-throughput screening

Abstract

The search for novel organic molecules with biological activity on human, animal, and plant physiological systems has passed through many phases over the centuries. From first steps testing single molecules on whole living systems to fully automated high-throughput screening (HTS) testing tens or hundreds of thousands of molecules per day on purified protein targets, the search has become ever more complex (1, 2). However, the increase in success has not been proportional to the effort and expense entailed. In particular, when considering the screening of “small molecules” (molecular mass <1,000 Da), the results of contemporary HTS have been plagued with problems of false positives, false negatives (3), and the abnormal behavior of certain molecules resulting from their physicochemical properties rather than their biological activity (4). In PNAS, Miller et al. (5) describe a significant evolution of current HTS technology that increases the confidence in the detection of truly active molecules by an order of magnitude.