Using the TanimotoCombo score, ROCS ranked the targets of interest of the natural products among the top-10 positions for only eight out of 48 queries (17%; the 48 queries result from the 38 unique natural products and natural product-like compounds). This success rate is considerably lower than the ones averaged over all 350 queries (36%), all 289 non-macrocyclic queries (38%) and all macrocyclic queries (25%), indicating that the prediction of the targets of complex natural products is more challenging than of complex synthetic molecules. A main reason for the low prediction success rates is the fact that the similarity of complex natural products and natural product-like compounds, and the non-CSM of the knowledge base is generally low.