Exploring the inhibitory properties of biflavonoids on α-glucosidase; computational and experimental approaches

Abstract

Biflavonoids (BFs) are a group of polyphenols that have a unique biochemical structure. One of the key biomedical mechanisms that BFs can have high potential in managing Diabetes mellitus (DM) is alpha-glucosidase inhibition. Normally, elevated blood glucose levels are caused by high absorption of glucose in the epithelium of the small intestine. Since alpha-glucosidase helps increase the absorption of glucose in the small intestine in the final stage of glycan catabolism, inhibition of this essential biochemical process in diabetic patients can be considered a suitable approach in the treatment of this disease. The interaction between the BFs and alpha-glucosidase are still not clear, and need to be deeply investigated. Herein, the aim is to identify BFs with strong alpha-glucosidase inhibitory activity. Using docking-based virtual screening approach, the potential binding affinity of 18 selected BFs to alpha-glucosidase was evaluated. The dynamic activity and stability of alpha-glucosidase-BFs complexes were then measured by molecular dynamics simulation (MDs). "Strychnobiflavone" showed the best score in alpha-glucosidase inhibition. Arg315 and Phe303 involved in the interactions of alpha-glucosidase-strychnobiflavone complex through cation-pi and pi-pi stacking, respectively. Based on in vitro kinetic studies, it was determined that the type of inhibition of "strychnobiflavone" corresponds to the pattern of mixed inhibitors. Furthermore, details of the interactions between strychnobiflavone and alpha-glucosidase were performed by in silico secondary structure content analysis. The findings showed when "strychnobifone" binds to the enzyme, significant alterations occur in the enzyme conformation affecting its catalytic activity. In general, the findings highlighted the potential of "strychnobiflavone" as a promising candidate for the treatment of diabetes mellitus through alpha-glucosidase inhibition. Further in vitro and in vivo studies have to confirm the therapeutic benefits of "strychnobiflavone" in conformational diseases such as diabetes mellitus.