Multidisciplinary structural optimization of polysaccharides preventing alcohol-induced liver disease with computer-aided molecular design

Here, we optimized the active units of polysaccharides and investigated the conformational relationship between the polysaccharides and alcoholic liver disease (ALD) at the molecular level. We used data mining to screen polysaccharide structural parameters for ALD (PSP-ALD). Most ALD-resistant polysaccharides against ALD comprised glucose (Glc), mannose (Man), galactose (Gal), arabinose (Ara), and rhamnose (Rha). Additionally, (1 → 6)-, (1 → 3)-, and (1 → 4)- glycosidic linkages were mainly contained. Polysaccharides against ALD have a wide molecular weight distribution (2.1 × 10 3  Da - 9.6 × 10 7  Da). Based on the PSP-ALD analysis, six commercially available oligosaccharides were selected and their structures were built. After molecular docking, the binding affinities between stachyose and the key ALD targets were stronger, indicating that stachyose may be a polysaccharide-active unit against ALD (PAU-ALD). Furthermore, histological examination of liver tissue combined with serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and triglycerides (TG) showed that stachyose had a significant protective effect against ALD in mice. In summary, we optimized a PAU-ALD and developed a method for studying the structure-activity relationship between polysaccharides and ALD at the molecular level, which provides a new research direction for the development and utilization of polysaccharides and their clinical applications in ALD.