Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking

Abstract

α-glucosidase inhibitors (AGIs) have been an important category of oral antidiabetic drugs being widely exploited for the effective management of type 2 diabetes mellitus. However, the marketed AGIs not only inhibited the disaccharidases, but also exhibited an excessive inhibitory effect on α-amylase, resulting in undesirable gastrointestinal side effects. Compared to these agents, Ramulus Mori alkaloids (SZ-A), was a group of effective alkaloids from natural Morus alba L., and showed excellent hypoglycemic effect and fewer side effects in the Phase II/III clinical trials. Thus, this paper aims to investigate the selective inhibitory effect and mechanism of SZ-A and its major active ingredients (1-DNJ, FA and DAB) on different α-glucosidases (α-amylase and disaccharidases) by using a combination of kinetic analysis and molecular docking approaches. From the results, SZ-A displayed a strong inhibitory effect on maltase and sucrase with an IC50 of 0.06 μg/mL and 0.03 μg/mL, respectively, which was similar to the positive control of acarbose with an IC50 of 0.07 μg/mL and 0.68 μg/mL. With regard to α-amylase, SZ-A exhibited no inhibitory activity at 100 μg/mL, while acarbose showed an obvious inhibitory effect with an IC50 of 1.74 μg/mL. The above analysis demonstrated that SZ-A could selectively inhibit disaccharidase to reduce hyperglycemia with a reversible competitive inhibition, which was primarily attributed to the three major active ingredients of SZ-A, especially 1-DNJ molecule. In the light of these findings, molecular docking study was utilized to analyze their inhibition mechanisms at molecular level. It pointed out that acarbose with a four-ring structure could perform desirable interactions with various α-glucosidases, while the three active ingredients of SZ-A, belonging to monocyclic compounds, had a high affinity to the active site of disaccharidases through forming a wide range of hydrogen bonds, whose affinity and consensus score with α-amylase was significantly lower than that of acarbose. Our study illustrates the selective inhibition mechanism of SZ-A on α-glucosidase for the first time, which is of great importance for the treatment of type 2 diabetes mellitus.

α-Glucosidase inhibitors from Chinese bayberry (Morella rubraSieb. et Zucc.) fruit: molecular docking and interaction mechanism of flavonols with different B-ring hydroxylations

“…5D), which was consistent with the previous reports. 54,55 In addition, the secondary plots (inset of Fig. 5A-C) of slope and Y-intercept against avonols concentrations were linearly tted, indicating that they bound in a single inhibition site or a single class of inhibition sites on a-glucosidase.…”

Phytochemical profile, enzyme inhibition activity and molecular docking analysis ofFeijoa sellowianaO. Berg

“…To gain insights into how the observed in vitro activity of Feijoa extract and its isolated compounds may be translated into therapeutic outcome, we used molecular docking to visualise ligand protein interactions of the isolated compounds in the active site of intestinal glucoamylase and pancreatic a-amylase; the two main a-glucosidases responsible for releasing glucose from dietary carbohydrate in the intestine 34,35 .…”

Ramulus Mori (Sangzhi) Alkaloids (SZ-A) Ameliorate Glucose Metabolism Accompanied by the Modulation of Gut Microbiota and Ileal Inflammatory Damage in Type 2 Diabetic KKAy Mice

“…SZ-A has also been shown to reduce the peak of postprandial blood glucose in sucrose/starch loading tests in both healthy and diabetic mice after a single dose through the inhibition of intestinal disaccharidases. Moreover, available evidence from our previous study suggests that SZ-A improves dyslipidemia and glucose-stimulated insulin secretion in high-fat diet-induced obese C57 mice after long-term intragastrical administration (Liu et al, 2019b). These data suggest that the beneficial role of SZ-A may involve multiple mechanisms in addition to α-glucosidase inhibition.…”