A chemoinformatic analysis on natural glycosides with respect to biological origin and structural class

Covering: up to 202216.19% of reported natural products (NPs) in the Dictionary of Natural Products (DNP) are glycosides. As one of the most important NPs' structural modifications, glycosylation can change the NPs' polarity, making the aglycones more amphipathic. However, until now, little is known about the general distribution profile of the natural glycosides in different biological sources or structural types. The reason, structural or species preferences of the natural glycosylation remain unclear. In this highlight, chemoinformatic methods were employed to analyze the natural glycosides from DNP, the most comprehensively annotated NP database. We found that the glycosylation ratios of NPs from plants, bacteria, animals and fungi decrease successively, which are 24.99%, 20.84%, 8.40% and 4.48%, respectively. Echinoderm-derived NPs (56.11%) are the most frequently glycosylated, while those produced by molluscs (1.55%), vertebrates (2.19%) and Rhodophyta (3.00%) are the opposite. Among the diverse structural types, a large proportion of steroids (45.19%), tannins (44.78%) and flavonoids (39.21%) are glycosides, yet aminoacids and peptides (5.16%), alkaloids (5.66%) are comparatively less glycosylated. Even within the same biological source or structural type, their glycosylation rates fluctuate drastically between sub- or cross-categories. The substitute patterns of flavonoid and terpenoid glycosides and the most frequently glycosylated scaffolds were identified. NPs with different glycosylation levels occupy different chemical spaces of physicochemical property and scaffold. These findings could help us to interpret the preference of NPs' glycosylation and investigate how NP glycosylation could aid NP-based drug discovery.