Frequent hitters: nuisance artifacts in high-throughput screening.

One of the major challenges in early drug discovery is the recognition of frequent hitters (FHs), that is, compounds that nonspecifically bind to a range of macromolecular targets or false positives caused by various types of assay interference. In this review, we survey the mechanisms underlying different types of FH, including aggregators, spectroscopic interference compounds (i.e., luciferase inhibitors and fluorescent compounds), reactive compounds, and promiscuous compounds. We also review commonly used experimental detection techniques and computational prediction models for FH identification. In addition, the rational applications of these computational filters are discussed. It is believed that, with the rational use of FH filters, the efficiency of drug discovery will be significantly improved.