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

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

  • Molecules. 2019 May 8;24(9):1776. doi: 10.3390/molecules24091776.
Zhihua Liu 1 Ying Yang 2 Wujun Dong 3 Quan Liu 4 Renyun Wang 5 Jianmei Pang 6 Xuejun Xia 7 Xiangyang Zhu 8 Shuainan Liu 9 Zhufang Shen 10 Zhiyan Xiao 11 Yuling Liu 12
Affiliations

Affiliations

  • 1 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. liuzhihua0207@163.com.
  • 2 Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. yangying@imm.ac.cn.
  • 3 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. dwujun@vip.sina.com.
  • 4 Pharmacology and Natural Medicine Research Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. popliu@imm.ac.cn.
  • 5 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. wry@imm.ac.cn.
  • 6 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. pangjm@tidepharm.com.
  • 7 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. xjxia@imm.ac.cn.
  • 8 Beijing Wehand-Bio Pharmaceutical Company Limited, 30 Tianfu Street, Beijing 102600, China. zhuxiangyang68@163.com.
  • 9 Pharmacology and Natural Medicine Research Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. liusn@imm.ac.cn.
  • 10 Pharmacology and Natural Medicine Research Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. shenzhuf@imm.ac.cn.
  • 11 Beijing Key Laboratory of Active Substance Discovery and Drug Ability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. xiaoz@imm.ac.cn.
  • 12 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing Key Laboratory of Drug Delivery Technology and Novel Formulation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China. ylliu@imm.ac.cn.
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.

Keywords

kinetics analysis; molecular docking; mulberry alkaloids; type 2 diabetes mellitus; α-glucosidase inhibitors.

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