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  • However it is unclear whether the parent

    2022-05-19

    However, it is unclear whether the parent and transition metal substitution in Keggin-type phosphomolybdic Fluorescein-12-dUTP will reveal the best effects on α-glucosidase. Therefore, the Keggin-type H3PMo12O40 (abbreviated as PMo12) and three transition metal-substituted POMs (Na4PMo11VO40, Na6PMo11FeO40 and Na7PMo11CoO40, abbreviated as PMo11V, PMo11Fe and PMo11Co) were synthesized and characterized. The inhibitory effect of these four compounds on α-glucosidase was studied by enzyme kinetics. In addition, to further study the binding forms and interactions of α-glucosidase and Keggin-type phosphomolybdic acid, the inhibitor PMo12 was used as a ligand for molecular docking simulation in the following studies. This work provided an enlightened strategy for expanding the applications of Keggin-type phosphomolybdic acid and for designing new and effective α-glucosidase inhibitors.
    Materials and methods
    Results and discussion
    Conclusions In summary, PMo12 and three transition metal-substituted Keggin-type phosphomolybdic acids (PMo11V, PMo11Fe and PMo11Co) could effectively inhibit α-glucosidase activity by enzyme kinetics, and the inhibitory effect of PMo12 was approximately 117 times higher than that of standard acarbose [41]. Moreover, combining the inhibition mechanism and the type of inhibition, we found that the inhibitors PMo12, PMo11V and PMo11Co showed reversible competitive inhibition of α-glucosidase, while PMo11Fe showed reversible noncompetitive inhibition of α-glucosidase. In addition, molecular modeling experiments showed that the inhibitor PMo12 mainly binds to the amino acid molecules of the active site in the α-glucosidase molecule through hydrogen bonding and van der Waals interaction. Therefore, the enzyme is not inactivated and the inhibition mechanism is reversible. According to the obtained experimental results above, we further demonstrated the results of enzyme kinetic experiments and further expound upon the mechanisms of action at the molecular level. This work provided an ideal strategy for designing α-glucosidase inhibitors with high efficiency, low cytotoxicity [32,43] and low cost. Due to the complex mechanisms of action of Keggin-type POMs with respect to α-glucosidase, the need for further research is emphasized. Through future experiments, we will determine the active site and substrate-binding mode of α-glucosidase by using site-directed mutagenesis and comparative modeling methods, and we will expand our investigation by analogous inhibition studies with the human α-glucosidase and the model enzyme isomaltase. In a sense, our work advances our understanding of the design and synthesis of Keggin-type phosphomolybdic acids as multifunctional therapeutic agents against type 2 diabetes. The following are the supplementary data related to this article.
    Acknowledgements This work was supported by the National Natural Science Foundation of China (Grant No. 21871110).
    Introduction Diabetes mellitus (DM) is a complicated chronic metabolic disorder caused by insufficient insulin secretion (type I DM) or inadequate utilization of insulin (type II DM) [1]. It is typically characterized by postprandial hyperglycemia, which will cause many complications including nephropathy, retinopathy, and cardiovascular diseases [2]. For reducing postprandial glucose level of blood, one of the most effective approach is to inhibit the activity of carbohydrate hydrolases, particularly α-glucosidase in the brush border of the small intestinal epithelial cells [3]. α-Glucosidase hydrolyzes α-1,4 glycosidic bond to release α-glucose from the non-reducing end of glucose multimers, which is the final step in the digestion of carbohydrates [[4], [5], [6]]. Hence, α-glucosidase inhibitors are effective in controlling postprandial hyperglycemia. By now, some α-glucosidase inhibitors have been applied clinically, such as acarbose, migltol, and voglibose. However, it has been reported that these anti-diabetic drugs often leaded to many side effects including flatulence, abdominal pain, diarrhea, and other gastrointestinal disorders [7,8]. Therefore, it is an urgent task to search for effective α-glucosidase inhibitors with fewer side effects.