A recent editorial (Aldrich et al. The Ecstasy and Agony of Assay Interference Compounds . J. Chem. Inf.
Model: 2017 , 57 , 387 - 390 ) is examined critically. When assessing assay hits from screening, it is important to draw a distinction between false positives, that have no effect on target function, and compounds that affect target function through an undesirable mechanism of action. Observation of frequent-hitter behavior for a compound should be regarded as circumstantial evidence, rather than definitive proof, that the compound has interfered with assay readouts or acted through an undesirable mechanism of action. The applicability domain of published (Baell and Holloway J. Med. Chem. 2010 , 53 , 2719 - 2740 ) Pan Assay INterference compoundS (PAINS) filters is limited by the narrow scope of the proprietary data used to derive them. It is suggested that journal guidelines for authors should not prescribe, as those for the Journal of Medicinal Chemistry appear to do, that activity in assays reported for compounds that match PAINS filters be treated any differently from that for compounds that do not match PAINS filters. It is argued that use of models based on proprietary data in the evaluation of manuscripts would contradict the editorial policy of any journal that deemed the use of proprietary data to be unacceptable in modeling studies.