Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking
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...
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MDPI AG
2019-05-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/24/9/1776 |
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| author | Zhihua Liu Ying Yang Wujun Dong Quan Liu Renyun Wang Jianmei Pang Xuejun Xia Xiangyang Zhu Shuainan Liu Zhufang Shen Zhiyan Xiao Yuling Liu |
| author_facet | Zhihua Liu Ying Yang Wujun Dong Quan Liu Renyun Wang Jianmei Pang Xuejun Xia Xiangyang Zhu Shuainan Liu Zhufang Shen Zhiyan Xiao Yuling Liu |
| author_sort | Zhihua Liu |
| collection | DOAJ |
| description | 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 <i>Morus alba</i> 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<sub>50</sub> of 0.06 μg/mL and 0.03 μg/mL, respectively, which was similar to the positive control of acarbose with an IC<sub>50</sub> 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<sub>50</sub> 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. |
| first_indexed | 2024-12-18T08:13:31Z |
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| spelling | doaj.art-cceae863aae943b4b7a5c9a9557984c02022-12-21T21:14:51ZengMDPI AGMolecules1420-30492019-05-01249177610.3390/molecules24091776molecules24091776Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular DockingZhihua Liu0Ying Yang1Wujun Dong2Quan Liu3Renyun Wang4Jianmei Pang5Xuejun Xia6Xiangyang Zhu7Shuainan Liu8Zhufang Shen9Zhiyan Xiao10Yuling Liu11State 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, ChinaBeijing 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, ChinaState 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, ChinaPharmacology and Natural Medicine Research Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, ChinaState 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, ChinaState 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, ChinaState 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, ChinaBeijing Wehand-Bio Pharmaceutical Company Limited, 30 Tianfu Street, Beijing 102600, ChinaPharmacology and Natural Medicine Research Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, ChinaPharmacology and Natural Medicine Research Laboratory, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, ChinaBeijing 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, ChinaState 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, Chinaα-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 <i>Morus alba</i> 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<sub>50</sub> of 0.06 μg/mL and 0.03 μg/mL, respectively, which was similar to the positive control of acarbose with an IC<sub>50</sub> 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<sub>50</sub> 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.https://www.mdpi.com/1420-3049/24/9/1776type 2 diabetes mellitusmulberry alkaloidsα-glucosidase inhibitorskinetics analysismolecular docking |
| spellingShingle | Zhihua Liu Ying Yang Wujun Dong Quan Liu Renyun Wang Jianmei Pang Xuejun Xia Xiangyang Zhu Shuainan Liu Zhufang Shen Zhiyan Xiao Yuling Liu Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking Molecules type 2 diabetes mellitus mulberry alkaloids α-glucosidase inhibitors kinetics analysis molecular docking |
| title | Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking |
| title_full | Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking |
| title_fullStr | Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking |
| title_full_unstemmed | Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking |
| title_short | Investigation on the Enzymatic Profile of Mulberry Alkaloids by Enzymatic Study and Molecular Docking |
| title_sort | investigation on the enzymatic profile of mulberry alkaloids by enzymatic study and molecular docking |
| topic | type 2 diabetes mellitus mulberry alkaloids α-glucosidase inhibitors kinetics analysis molecular docking |
| url | https://www.mdpi.com/1420-3049/24/9/1776 |
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