Molecular interactions with redox sites and salt bridges modulate the anti-aggregatory effect of flavonoid, tannin and cardenolide moieties against amyloid-beta (1-42) in silico.

In this study, the interactions of flavonoid, tannin and cardenolide moieties as well as their known metabolites were docked against the apolar NMR structure of the aggregatory amyloid-beta fragment (Aβ1-42). Results showed that the catechin moiety favorably bound Aβ1-42 peptide at Asp23, Asn27, Ser26 and Glu22 residues, with chalcone similarly binding the middle region of the peptide. Remarkably, hippuric and ferulic acids exhibited hydrophobic interactions with Aβ1-42 at the latter portion of the peptide, possibly blocking the salt bridges formed by Glu22-Lys28 which stabilizes Phe19-Gly25, as well as the β-sheet Leu34-Gly38 that are known to exist in peptide aggregation. Meanwhile, the metabolites of hydrolyzable tannins, such as urolithin A and gallic acid, exhibited H-bonding interactions with different residues of Aβ1-42, including Asp1, Asp23 and hydrophobic interactions by gallic acid planar ring to the Hsd6 residue. The coverage was lessened in pyrogallol, suggesting that gallic acid loses its efficacy when further metabolized. Lastly, the different binding poses of the cardenolide moiety interacted with Hsp6 (protonated His) and Tyr10 via hydrophobic interactions. Due to these interactions, the large polycyclic moiety of the ligand would also block further interactions with Hsd6 (prototropic tautomer of His), Asp7, Ser8 and Gly9 that are integral to His6-His13-His14, Arg5-Asp7and Leu34-Gly38 β-sheets, salt bridges in Glu22-Lys28 and turn conformation Phe19-Gly25. Together, these data suggest that the known metabolites of anthocyanins and hydrolyzable tannins contribute the most effective anti-aggregatory interactions with Aβ1-42, with an unexpected role for cardiac glycosides such as the cardenolie moiety. These bring to light the important role of metabolism in vivo, and suggests further investigation on the effects of these metabolites when concentrated in vivo.