Discovery of natural adenosine monophosphate‑activated protein kinase activators through virtual screening and activity verification studies

Jia, Hao; Li, Jian; Han, Lifeng; Zhang, Yi; Wang, Tao

doi:10.3892/mmr.2021.11842

Cited by 5 publications

(3 citation statements)

References 26 publications

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“…Due to the essential role of AMPK on glucose and lipid metabolism, the exploration of molecules that can activate AMPK is an emerging field both in pharmacology and nutrition (Grahame Hardie, 2016; Hao et al , 2021; Olivier et al , 2018). Several bioactive compound such as phenolic compound and polyphenols have been reported to activate AMPK and ameliorate glucose uptake in insulin resistance condition (Huang et al , 2015; Vazirian et al , 2018; Momtaz et al , 2019).…”

Section: Discussionmentioning

confidence: 99%

Effect of fermented cassava tuber on the gene expression of PI3K/Akt signaling and AMPK pathway in STZ-NA-induced diabetic rats

Kusuma

Puspaningtyas

Sari

2022

NFS

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Purpose The downstream insulin signaling, such as phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) pathway, is an important step for skeletal glucose disposal through the translocation of glucose transporter (GLUT)-4. In addition, the master of energy regulator adenosine monophosphate-activated kinase (AMPK) is also involved in GLUT-4 translocation, independent from the PI3K/Akt pathway. Fermented cassava tuber or gatot is a traditional food from Indonesia with antihyperglycemic properties. However, the molecular mechanism leading to this effect is unclear. Therefore, this paper aims to evaluate whether the antidiabetic activity of gatot is through PI3K/Akt dependent or AMPK pathway. Design/methodology/approach Diabetes mellitus was induced in 20 male Wistar rats by intraperitoneal injection of 65 mg/kg body weight streptozotocin and 230 mg/kg body weight nicotinamide. Diabetic rats were randomly allocated into four groups; negative control, positive control (metformin 100 mg/kg body weight), fermented cassava diet replacing 50% of carbohydrate (FC-50) and 100% of carbohydrate (FC-100) in the diet. Serum glucose, insulin and lipid profile were analyzed before and after four weeks of intervention. Genes expression of PI3K subunit alpha, PI3K subunit beta, PI3K regulatory subunit, Akt and AMPK were analyzed using real time polymerase chain reaction (PCR). GLUT-4 protein expression was performed using immunohistochemistry. Findings There is a significant difference (p = 0.000) in serum glucose, insulin, total cholesterol, triglyceride, high density lipoprotein (HDL)-cholesterol and LDL-cholesterol between groups. Skeletal AMPK gene expression was higher and significantly different between FC-100 (p = 0.006) and healthy control groups. No significant difference was observed in the messenger ribonucleic acid (mRNA) expression of the PI3K/Akt pathway among groups. GLUT-4 expression was highly expressed in a positive control group followed by FC-100. Research limitations/implications This paper did not characterize the bioactive component that is responsible for increasing mRNA expression of AMPK. This paper also did not analyze the phosphorylation of PI3K/Akt and AMPK that are important in activating the protein. Originality/value To the best of the authors’ knowledge, this is the first study that showed the antidiabetic activity of traditional fermented food is through AMPK-dependent activity.

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Section: Discussionmentioning

confidence: 99%

Effect of fermented cassava tuber on the gene expression of PI3K/Akt signaling and AMPK pathway in STZ-NA-induced diabetic rats

Kusuma

Puspaningtyas

Sari

2022

NFS

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“…In the literature (PubMed search with terms "AMPK" and "QSAR"), several QSAR models for prediction of AMPK activation have been published so far [24][25][26][27][28][29][30]. However, all of these models used pharmacophore docking analyses or homology models or structure-, ligand-, or fragment-based design and focused exclusively on direct AMPK activators.…”

Section: Discussionmentioning

confidence: 99%

Modeling Structure–Activity Relationship of AMPK Activation

Drewe

Küsters²,

Hammann

et al. 2021

Molecules

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The adenosine monophosphate activated protein kinase (AMPK) is critical in the regulation of important cellular functions such as lipid, glucose, and protein metabolism; mitochondrial biogenesis and autophagy; and cellular growth. In many diseases—such as metabolic syndrome, obesity, diabetes, and also cancer—activation of AMPK is beneficial. Therefore, there is growing interest in AMPK activators that act either by direct action on the enzyme itself or by indirect activation of upstream regulators. Many natural compounds have been described that activate AMPK indirectly. These compounds are usually contained in mixtures with a variety of structurally different other compounds, which in turn can also alter the activity of AMPK via one or more pathways. For these compounds, experiments are complicated, since the required pure substances are often not yet isolated and/or therefore not sufficiently available. Therefore, our goal was to develop a screening tool that could handle the profound heterogeneity in activation pathways of the AMPK. Since machine learning algorithms can model complex (unknown) relationships and patterns, some of these methods (random forest, support vector machines, stochastic gradient boosting, logistic regression, and deep neural network) were applied and validated using a database, comprising of 904 activating and 799 neutral or inhibiting compounds identified by extensive PubMed literature search and PubChem Bioassay database. All models showed unexpectedly high classification accuracy in training, but more importantly in predicting the unseen test data. These models are therefore suitable tools for rapid in silico screening of established substances or multicomponent mixtures and can be used to identify compounds of interest for further testing.

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“…47 Similarly, a previous study proposed that AMPK activators should possess a favorable feature, which is the formation of a salt bridge with Lys29. 48 Furthermore, a former in vitro study has shown the potential of beta-sitosterol as an AMPK activator, by increasing the expression of AMPK in L6 myotube cells. 49 Thienopyridone (synonym A-769662) and metformin were used as standards because these two drugs are well-known as AMPK activators.…”

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confidence: 99%

Molecular Docking Study of Phytosterols in Lygodium microphyllum Towards SIRT1 and AMPK, the in vitro Brine Shrimp Toxicity Test, and the Phenols and Sterols Levels in the Extract

Anggreini,

Kuncoro,

Sumiwi

et al. 2023

JEP

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Background Lygodium microphyllum is a fern plant with various pharmacological activities, and phytosterols were reported contained in the n-hexane and ethyl acetate extract of this plant. Phytosterols are known to inhibit steatosis, oxidative stress, and inflammation. Sirtuin 1 (SIRT1) and adenosine monophosphate-activated protein kinase (AMPK) are the key proteins that control lipogenesis. However, information about L. microphyllum on SIRT1 and AMPK is still lacking. Purpose This study aims to investigate the binding mode of phytosterols in L. microphyllum extract towards AMPK and SIRT1, and the toxicity of the extract against brine shrimp ( Artemia salina ) larvae, and to determine the phenols and sterols levels in the extract. Methods The molecular docking was performed towards SIRT1 and AMPK using AutoDock v4.2.6, the toxicity of the extract was assayed against brine shrimp ( Artemia salina ) larvae, and the phytosterols were analyzed by employing a thin layer chromatography densitometry, and the total phenols were by spectrophotometry. Results The molecular docking study revealed that β-sitosterol and stigmasterol could occupy the active allosteric-binding site of SIRT1 and AMPK by binding to important residues similar to the protein’s activators. The cold extraction of the plant yields 15.86% w/w. Phytochemical screening revealed the presence of phenols, steroids, flavonoids, alkaloids, and saponins. The total phenols are equivalent to 126 mg gallic acid (GAE)/g dry extract, the total sterols are 954.04 µg/g, and the β-sitosterol level is 283.55 µg/g. The LC 50 value of the extract towards A. salina larvae is 203.704 ppm. Conclusion Lygodium microphyllum extract may have the potential to be further explored for its pharmacology activities, particularly in the discovery of plant-based anti-dyslipidemic drug candidates. However, further studies are needed to confirm their roles in alleviating lipid disorders.

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Discovery of natural adenosine monophosphate‑activated protein kinase activators through virtual screening and activity verification studies

Cited by 5 publications

References 26 publications

Effect of fermented cassava tuber on the gene expression of PI3K/Akt signaling and AMPK pathway in STZ-NA-induced diabetic rats

Effect of fermented cassava tuber on the gene expression of PI3K/Akt signaling and AMPK pathway in STZ-NA-induced diabetic rats

Modeling Structure–Activity Relationship of AMPK Activation

Molecular Docking Study of Phytosterols in Lygodium microphyllum Towards SIRT1 and AMPK, the in vitro Brine Shrimp Toxicity Test, and the Phenols and Sterols Levels in the Extract

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