Structural Diversity and Chemical Space of Natural Product Substituents Across Different Organism Groups

<jats:p>Natural products represent one of the richest sources of biologically active compounds and occupy regions of chemical space that are distinct from those of synthetic molecules. While the global structural characteristics of natural products have been extensively studied, less attention has been given to the diversity and distribution of substituents attached to their central scaffolds. Here, we analyze the structural diversity and chemical space of substituents found in natural products from six organism groups: plants, fungi, bacteria, animals, sponges, and corals. Analysis of 22,713 unique substituents derived from approximately 273,000 natural products revealed distinct organism-specific patterns in substituent composition. Plant metabolites are enriched in oxygen-containing substituents, particularly methoxy, hydroxyl, and glycosidic motifs. Bacterial metabolites show the greatest prevalence of nitrogen-containing functionalities, including amines, amides, and guanidines, as well as sulfur-containing groups. Marine organisms, particularly sponges and corals, display elevated frequencies of halogenated substituents, especially brominated motifs. These findings provide a basis for natural product-inspired molecular design and can support the rational generation of pseudo-natural products and compound libraries enriched in biologically relevant structural features.</jats:p>