Many approved drugs have bioactive analogs with different target annotations.

Close structural relationships between approved drugs and bioactive compounds were systematically assessed using matched molecular pairs. For structural analogs of drugs, target information was assembled from ChEMBL and compared to drug targets reported in DrugBank. For many drugs, multiple analogs were identified that were active against different targets. Some of these additional targets were closely related to known drug targets while others were not. Surprising discrepancies between reported drug targets and targets of close structural analogs were often observed. On one hand, the results suggest that hypotheses concerning alternative drug targets can often be formulated on the basis of close structural relationships to bioactive compounds that are easily detectable. It is conceivable that such obvious structure-target relationships are frequently not considered (or might be overlooked) when compounds are developed with a focus on a primary target and a few related (or undesired) ones. On the other hand, our findings also raise questions concerning database content and drug repositioning efforts.