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Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking.
Molecules 2019; 24(9)M

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.

Authors+Show Affiliations

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.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.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.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.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.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.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.Beijing Wehand-Bio Pharmaceutical Company Limited, 30 Tianfu Street, Beijing 102600, China. zhuxiangyang68@163.com.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.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.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.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31071910

Citation

Liu, Zhihua, et al. "Investigation On the Enzymatic Profile of Mulberry Alkaloids By Enzymatic Study and Molecular Docking." Molecules (Basel, Switzerland), vol. 24, no. 9, 2019.
Liu Z, Yang Y, Dong W, et al. Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking. Molecules. 2019;24(9).
Liu, Z., Yang, Y., Dong, W., Liu, Q., Wang, R., Pang, J., ... Liu, Y. (2019). Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking. Molecules (Basel, Switzerland), 24(9), doi:10.3390/molecules24091776.
Liu Z, et al. Investigation On the Enzymatic Profile of Mulberry Alkaloids By Enzymatic Study and Molecular Docking. Molecules. 2019 May 8;24(9) PubMed PMID: 31071910.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking. AU - Liu,Zhihua, AU - Yang,Ying, AU - Dong,Wujun, AU - Liu,Quan, AU - Wang,Renyun, AU - Pang,Jianmei, AU - Xia,Xuejun, AU - Zhu,Xiangyang, AU - Liu,Shuainan, AU - Shen,Zhufang, AU - Xiao,Zhiyan, AU - Liu,Yuling, Y1 - 2019/05/08/ PY - 2019/04/22/received PY - 2019/05/04/revised PY - 2019/05/05/accepted PY - 2019/5/11/entrez PY - 2019/5/11/pubmed PY - 2019/8/30/medline KW - kinetics analysis KW - molecular docking KW - mulberry alkaloids KW - type 2 diabetes mellitus KW - α-glucosidase inhibitors JF - Molecules (Basel, Switzerland) JO - Molecules VL - 24 IS - 9 N2 - 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. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/31071910/Investigation_on_the_Enzymatic_Profile_of_Mulberry_Alkaloids_by_Enzymatic_Study_and_Molecular_Docking L2 - http://www.mdpi.com/resolver?pii=molecules24091776 DB - PRIME DP - Unbound Medicine ER -