Revealing the Macromolecular Targets of Fragment-Like Natural Products

Fragment‐like natural products were identified as ligand‐efficient chemical matter for hit‐to‐lead development and chemical‐probe discovery. Relying on a computational method using a topological pharmacophore descriptor and a drug database, several macromolecular targets from distinct protein families were expeditiously retrieved for structurally unrelated chemotypes. The selected fragments feature structural dissimilarity to the reference compounds and suitable target affinity, and they offer opportunities for chemical optimization. Experimental confirmation of hitherto unknown macromolecular targets for the selected molecules corroborate the usefulness of the computational approach and suggests broad applicability to chemical biology and molecular medicine. Target acquired: Hitherto unknown macromolecular targets of the fragment‐like natural products goitrin, isomacroin, and graveolinine were discovered through the use of a computational target‐prediction tool tailored for natural products. The results suggest that such methods will find application in target discovery for natural products and could inspire the design of new chemical entities for chemical biology and molecular medicine.