GSH reactivity predictions for compounds in DrugBank and PubChem. PAINS filters are associated with increased GSH reactivity scores in PubChem, but reactivity is not increased among FDA-approved drugs. (A) Reactivity scores for FDA-approved drugs in DrugBank are comparable between PAINS and non-PAINS, whereas reactivity scores of PubChem PAINS matches are substantially elevated compared to non-PAINS and compared to DrugBank (p = 2.06 × 10−7, Mann–Whitney U-test). While some FDA-approved drugs act via a reactive mechanism, the majority of FDA-approved drugs are not explicitly reactive and not found to be promiscuous bioactives. Outliers are not shown. (B) Compounds active in more than 5% of tested assays in PubChem have substantially higher reactivity scores than nonpromiscuous compounds (p < 10−10, Mann–Whitney U-test). Outliers are not shown. **: p < 0.001. ***: p < 0.0001.