Targeting galectin-3 by natural glycosides: a computational approach

As a carbohydrate-binding protein, galectin-3 represented as a potential target for numerous therapeutic inventions, as it controls cell proliferation, promotes inflammatory responses, inhibits apoptosis, and a negative regulator of memory formation. The regulations by galectin-3 can be blocked by the compounds having the multivalent presentation of carbohydrate (galactose) derivatives; therefore, the present study focused on the natural glycosides to find a potent inhibitor with reduced toxicity. Here, we introduced a computational pipeline by integrating molecular docking, steered molecular dynamics simulation and molecular dynamics simulation to screen out potential compounds from a library of the natural glycoside. Based on structure mediated virtual screening protocol involving molecular docking and MM-GBSA analysis, four natural glycosides were selected and considered for further induced fit docking (IFD) and steered molecular dynamics simulation approach. According to the docking analysis, all compounds made polar interactions with Glu184, Arg162, His158 and Asn174, while the only spiraeoside showed hydrogen bond with Arg144, a non-conserved residue than other members of galectin family. Interestingly, spiraeoside also showed maximum unbinding energy in steered molecular dynamics simulation which eventually supported the binding free energy analysis by MM-GBSA. Furthermore, the specificity of spiraeoside towards galectin-3 was proved by water-bridge interaction with Arg144 residue in molecular dynamics simulation. Finally, this study highlights the potentiality of natural glycosides as a galectin-3 inhibitor, remarking spiraeoside, which could be a potent inhibitor, and can be considered for future research to develop the new drug against galectin-3.