biomolecules Article Description and Analysis of Glycosidic Residues in the Largest Open Natural Products Database Jonas Schaub 1 , Achim Zielesny 2 , Christoph Steinbeck 1, * and Maria Sorokina 1, *   Citation: Schaub, J.; Zielesny, A.; Steinbeck, C.; Sorokina, M. Description and Analysis of Glycosidic Residues in the Largest Open Natural Products Database. Biomolecules 2021, 11, 486. https:// doi.org/10.3390/biom11040486 Academic Editor: José L. Medina-Franco Received: 26 February 2021 Accepted: 21 March 2021 Published: 24 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Institute for Inorganic and Analytical Chemistry, Friedrich-Schiller University, Lessing Strasse 8, 07743 Jena, Germany; jonas.schaub@uni-jena.de 2 Institute for Bioinformatics and Chemoinformatics, Westphalian University of Applied Sciences, August-Schmidt-Ring 10, 45665 Recklinghausen, Germany; achim.zielesny@w-hs.de * Correspondence: christoph.steinbeck@uni-jena.de (C.S.); maria.sorokina@uni-jena.de (M.S.) Abstract: Natural products (NPs), biomolecules produced by living organisms, inspire the pharma- ceutical industry and research due to their structural characteristics and the substituents from which they derive their activities. Glycosidic residues are frequently present in NP structures and have particular pharmacokinetic and pharmacodynamic importance as they improve their solubility and are often involved in molecular transport, target specificity, ligand–target interactions, and receptor binding. The COlleCtion of Open Natural prodUcTs (COCONUT) is currently the largest open database of NPs, and therefore a suitable starting point for the detection and analysis of the diversity of glycosidic residues in NPs. In this work, we report and describe the presence of circular, linear, terminal, and non-terminal glycosidic units in NPs, together with their importance in drug discovery. Keywords: natural products; glycosides; bioactivity; glycosidic residues; sugars; carbohydrates; deglycosylation; cheminformatics; Chemistry Development Kit; CDK 1. Introduction Natural products (NPs) are biologically active molecules produced by living organ- isms. Their importance for the producing organisms themselves and for their interaction with their environment as well as for therapeutical and agricultural usages is widely accepted [1–3]. Many NPs are glycosides, which means that in addition to their main structure (the aglycon), they contain one or several glycosidic substructures. For the glyco- sylated NP, the sugar residues can be crucial for their bioactivity, and when it is dispensable, they improve the pharmacokinetic parameters of the molecule [4]. Important classes of natural compounds are glycosides, such as hormones, alkaloids, polyketides, flavonoids, or antibiotics. Due to the hydrophilic structures of their sugar moieties, glycosides tend to be more water-soluble than their aglycons [4], which influences their pharmacokinetic properties, such as their concentration, circulation, and elimination in the human body fluids. However, this increased hydrophilicity mainly influences negatively the transport of the molecules through membranes, as hydrophobic compounds tend to enter cells due to their solubility in lipids. On the other hand, some glycosides can be actively transported into tissues and cells using the glucose transport system. Streptomycin (Figure 1a), an antibiotic isolated in 1943 by Albert Schatz from the bacterium Streptomyces griseus and still used in the present day, is a good example of the impact of a glycoside on the bioactivity of the molecule. The amino groups of the sugar rings of this antibiotic class bind to ribosomal RNA, causing a decrease in translation and translational accuracy and inhibit the translocation of the ribosome [5,6]. Aureolic acids are a group of antibiotics with one or several particular sugar moieties, D-olivose, attached to the aglycon (in Figure 1b, olivomycin A, a member of the aureolic acid family) and are known to inhibit the DNA-dependent RNA polymerase. Members of this group Biomolecules 2021, 11, 486. https://doi.org/10.3390/biom11040486 https://www.mdpi.com/journal/biomolecules