Inhibition Mechanism of Components Isolated from Morus alba Branches on Diabetes and Diabetic Complications via Experimental and Molecular Docking Analyses

• Published in: Antioxidants Vol. 11; no. 2; p. 383
• Main Authors: Kwon, Ryeong-Ha, Thaku, Niha, Timalsina, Binod, Park, Se-Eun, Choi, Jae-Sue, Jung, Hyun-Ah
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 14.02.2022; MDPI
• Subjects: Acarbose; Advanced glycosylation end products; Allosteric properties; Antioxidants; Chromatography; Column chromatography; Computer applications; Diabetes; Diabetes mellitus; enzyme kinetic; Enzyme kinetics; Flavonoids; Glucose; Glycosylation; Hyperglycemia; Hypoglycemia; Insulin resistance; Metabolism; molecular docking analysis; Morus alba; Peroxynitrite; Phosphorylation; protein tyrosine phosphatase 1B; Protein-tyrosine-phosphatase; Proteins; Resorcinol; Signal transduction; Solvents; structure–activity relationship; α-Glucosidase; South Korea; St Louis Missouri; United States > US; Japan; Germany; molecular docking analysis; structure–activity relationship; α-glucosidase; protein tyrosine phosphatase 1B; Morus alba; enzyme kinetic
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox11020383

Previously, we reported the anti-diabetic effect of root bark and the compounds therein. In our continuous study of other parts of this plant, the ability of the branch of to inhibit α-glucosidase, protein tyrosine phosphatase 1B (PTP1B), and advanced glycation end products (AGEs) formation was evaluated. Moreover, there are no previous studies that have performed enzyme kinetics and molecular docking analyses, along with assessments of peroxynitrite (ONOO ) inhibitory activities. Since the branch exhibited favorable inhibitory effects, repeated column chromatography was performed to obtain eight compounds, including four flavonoids ( , , ), one arylbenzofuran ( ), one stilbene ( ), one Diels-Alder-type adduct ( ), and one sterol ( ). Among them, compounds - and - were mixed-type inhibitors of α-glucosidase, sharing the same catalytic residues with acarbose and the same allosteric sites with (Z)-3-bytylidenephthalide. On the other hand, kuwanon C ( ) and oxyresveratrol ( ) interacted with residues of the allosteric site ( 3 and 6 helices) of PTP1B, indicating their use as non-competitive inhibitors. Interestingly, kuwanon G ( ) directly bound the catalytic site, or interrupted the binding between the substrate and the active site, as a mixed-type inhibitor. Moreover, most of the compounds exhibited greater activity against AGE formation and ONOO than positive controls. The IC values required to inhibit ONOO using compounds , , , , and were reported for the first time, and range from 1.08 to 12.92 μM. Based on the structure-activity relationship, the presence of hydroxyl, resorcinol, and prenyl moieties was important in the prevention of diabetes' pathological mechanisms, and these findings have been further supported by molecular docking analysis. These computational and experimental results will be useful in the development of therapeutic candidates to prevent/treat diabetes and its complications.