Figure 1.

Structural alerts (highlighted in red) incorrectly flag safe drugs because they do not adequately model metabolism. Known sites of metabolism are marked with white circles. The metabolism and reactivity⁹¹ predictions are plotted against each atom in the molecule, with color shading ranging from red (1.0, likely) to white (0.0, unlikely). Structural alerts indiscriminately flag both bioactivated and not-bioactivated compounds as problematic. For example, both methapyrilene and eprosartan contain the thiophene structural alert, yet their toxicity profiles are very different, as predicted by metabolism models (atom shading). While methapyrilene, an antacid, was withdrawn from the market due to hepatotoxicity caused by reactive metabolites,⁷⁶ eprosartan is a safe antihypertensive that does not form reactive metabolites.⁸²