Many structurally related drugs bind different targets whereas distinct drugs display significant target overlap

Currently available drugs and bioactive compounds have been subjected to a detailed analysis of their structural and target relationships. When single rings are excluded from structural analysis, due to their generic character, similar to 65% of all drugs are found to be involved in substructure relationships and/or are topologically equivalent. Furthermore, most targets of experimental drugs differ from targets of approved drugs. Surprisingly, only a small number of all drugs that share the same or overlapping targets are structurally related. Moreover, structurally similar drugs often act against distinct targets. In bioactive compounds, essentially opposite trends were observed. Thus, on the basis of our systematic analysis, structural and target relationships between drugs depart from the intuitive assumption that similar compounds should have similar activities, which is widely accepted in medicinal chemistry. Possible explanations for these rather unexpected findings are discussed.