Dataset Information

Aspulvinones Suppress Postprandial Hyperglycemia as Potent α-Glucosidase Inhibitors From Aspergillus terreus ASM-1.

ABSTRACT: Chemical investigation of Aspergillus terreus ASM-1 fermentation resulted in the isolation of three new prenylated aspulvinones V-X (1-3), together with the previously reported analogs, aspulvinone H (4), J-CR (5), and R (6). Their structures were elucidated by various spectroscopic methods including HRESIMS and NMR, and the absolute configurations of 2 and 3 were determined by ECD comparison. Compounds 1-6 were evaluated for α-glucosidase inhibitory effects with acarbose as positive control. As a result, compounds 1 and 4 exhibited potent α-glucosidase inhibitory activities with IC₅₀ values of 2.2 and 4.6 µM in mixed-type manners. The thermodynamic constants recognized the interaction between inhibitors and α-glucosidase was hydrophobic force-driven spontaneous exothermic reaction. The CD spectra also indicate that the compounds 1 and 4 changed the enzyme conformation. Furthermore, compound 4 significantly suppressed the increases in postprandial blood glucose levels in the C57BL/6J mice.

SUBMITTER: Wu C

PROVIDER: S-EPMC8416056 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Aspulvinones Suppress Postprandial Hyperglycemia as Potent α-Glucosidase Inhibitors From Aspergillus terreus ASM-1.

Wu Changjing C Cui Xiang X Sun Luzhen L Lu Jiajia J Li Feng F Song Minghui M Zhang Yunxia Y Hao Xinqi X Tian Congkui C Song Maoping M Liu Xiaomeng X

Frontiers in chemistry 20210817

Chemical investigation of Aspergillus terreus ASM-1 fermentation resulted in the isolation of three new prenylated aspulvinones V-X (1-3), together with the previously reported analogs, aspulvinone H (4), J-CR (5), and R (6). Their structures were elucidated by various spectroscopic methods including HRESIMS and NMR, and the absolute configurations of 2 and 3 were determined by ECD comparison. Compounds 1-6 were evaluated for ...[more]

PMID: 34485249

Similar Datasets

Project description:Background/Objectives: BuZhong YiQi Formula (BZYQF) can alleviate type 2 diabetes mellitus (T2DM). However, its efficacy in managing postprandial hyperglycemia in T2DM needs to be further confirmed, and its underlying mechanism and pharmacodynamic material basis have not been sufficiently investigated. Methods: A T2DM rat model was induced to measure postprandial glycemic responses following glucose and starch ingestion. In vitro assays of enzymatic inhibition and the kinetic mode were performed to evaluate the inhibitory effect of BZYQF on α-amylase and α-glucosidase activities. The main constituent contents of BZYQF in a simulated digestion assay were measured to screen the active constituents in BZYQF against α-amylase and α-glucosidase activities via Pearson correlation and multiple linear regression analyses. Finally, the total flavonoids were purified from BZYQF to perform in vitro activity validation, and the flavonoid constituent activity was verified through molecular docking. Results: In vivo assays showed that BZYQF significantly reduced the blood glucose values of CON rats but not T2DM rats after glucose ingestion, while BZYQF significantly reduced the blood glucose levels by 15 min after starch ingestion in CON and T2DM rats, with more significant decreases in blood glucose levels in T2DM rats. In vitro enzymatic assays showed that BZYQF could inhibit the activities of α-amylase and α-glucosidase in competitive and non-competitive modes and in an uncompetitive mode, respectively. Furthermore, BZYQF showed a stronger inhibitory effect on α-glucosidase activity than on α-amylase activity. Simulated digestion showed that simulated gastric fluid and intestinal fluid changed the main constituent contents of BZYQF and their inhibition rates against α-amylase and α-glucosidase activities, and similar results were rarely found in simulated salivary fluid. Pearson correlation and multiple linear regression analyses revealed that the total flavonoids were the active constituents in BZYQF inhibiting α-amylase and α-glycosidase activities. This result was verified by examining the total flavonoids purified from BZYQF. A total of 1909 compounds were identified in BZYQF using UPLC-MS/MS, among which flavones were the most abundant and consisted of 467 flavonoids. Molecular docking showed that flavonoids in BZYQF were bound to the active site of α-amylase, while they were bound to the inactive site of α-glucosidase. This result supported the results of the enzyme kinetic assay. Conclusions: BZYQF significantly alleviated postprandial hyperglycemia in T2DM rats by inhibiting α-amylase and α-glycosidase activities, in which flavonoids in BZYQF were the active constituents.

Project description:Hyperglycemia, as a hallmark of the metabolic malady diabetes mellitus, has been an overwhelming healthcare burden owing to its high rates of comorbidity and mortality, as well as prospective complications affecting different body organs. Available therapeutic agents, with α-glucosidase inhibitors as one of their cornerstone arsenal, control stages of broad glycemia while showing definitive characteristics related to their low clinical efficiency and off-target complications. This has propelled the academia and industrial section into discovering novel and safer candidates. Herein, we provided a thorough computational exploration of identifying candidates from the marine-derived Aspergillus terreus isolates. Combined structural- and ligand-based approaches using a chemical library of 275 metabolites were adopted for pinpointing promising α-glucosidase inhibitors, as well as providing guiding insights for further lead optimization and development. Structure-based virtual screening through escalating precision molecular docking protocol at the α-glucosidase canonical pocket identified 11 promising top-docked hits, with several being superior to the market drug reference, acarbose. Comprehensive ligand-based investigations of these hits' pharmacokinetics ADME profiles, physiochemical characterizations, and obedience to the gold standard Lipinski's rule of five, as well as toxicity and mutagenicity profiling, proceeded. Under explicit conditions, a molecular dynamics simulation identified the top-stable metabolites: butyrolactone VI (SK-44), aspulvinone E (SK-55), butyrolactone I 4''''-sulfate (SK-72), and terrelumamide B (SK-173). They depicted the highest free binding energies and steadiest thermodynamic behavior. Moreover, great structural insights have been revealed, including the advent of an aromatic scaffold-based interaction for ligand-target complex stability. The significance of introducing balanced hydrophobic/polar moieties, like triazole and other bioisosteres of carboxylic acid, has been highlighted across docking, ADME/Tox profiling, and molecular dynamics studies for maximizing binding interactions while assuring safety and optimal pharmacokinetics for targeting the intestinal-localized α-glucosidase enzyme. Overall, this study provided valuable starting points for developing new α-glucosidase inhibitors based on nature-derived unique scaffolds, as well as guidance for prospective lead optimization and development within future pre-clinical and clinical investigations.

Dataset Information

Aspulvinones Suppress Postprandial Hyperglycemia as Potent α-Glucosidase Inhibitors From Aspergillus terreus ASM-1.

Publications

Aspulvinones Suppress Postprandial Hyperglycemia as Potent α-Glucosidase Inhibitors From <i>Aspergillus terreus</i> ASM-1.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets