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

• Published in: Molecules (Basel, Switzerland) Vol. 24; no. 9; p. 1776
• Main Authors: Liu, Zhihua, Yang, Ying, Dong, Wujun, Liu, Quan, Wang, Renyun, Pang, Jianmei, Xia, Xuejun, Zhu, Xiangyang, Liu, Shuainan, Shen, Zhufang, Xiao, Zhiyan, Liu, Yuling
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 08.05.2019; MDPI
• Subjects: Acarbose; Affinity; Alkaloids; Alkaloids - chemistry; Alkaloids - metabolism; alpha-Glucosidases - metabolism; Amylases; Animals; Antidiabetics; Carbohydrates; Catalytic Domain; Clinical trials; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Enzyme kinetics; Glucosidase; Glycoside Hydrolase Inhibitors - chemistry; Glycoside Hydrolase Inhibitors - pharmacology; Hydrogen bonding; Hydrogen bonds; Hyperglycemia; Ingredients; Kinetics; kinetics analysis; Ligands; Molecular docking; Molecular Docking Simulation; Morus - chemistry; mulberry alkaloids; Rats, Wistar; Ring structures; Side effects; Solvents; Sucrase - metabolism; type 2 diabetes mellitus; α-Amylase; α-Glucosidase; α-glucosidase inhibitors; type 2 diabetes mellitus; α-glucosidase inhibitors; mulberry alkaloids; molecular docking; kinetics analysis
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules24091776

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 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 IC of 0.06 μg/mL and 0.03 μg/mL, respectively, which was similar to the positive control of acarbose with an IC 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 IC 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.