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Glycogen synthase, an enzyme that is responsible in glycogen synthesis, is activated by glucose 6-phosphate (G6P), and inhibited by glycogen synthase kinases (GSK3). Those two mechanisms play an important role in glycogen metabolism. Glycogen synthase kinase (GSK-3) is a serine/threonine kinase that phosphorylate either threonine or serine, and this phosphorylation permits a variety of biological activities as glycogen metabolism, cell signaling, cellular transport, and others. GS inhibition by GSK-3β leads to a decrease in glycogen synthesis in the liver and muscles, along with increased blood glucose or hyperglycemia. This is why GSK-3β is associated with the pathogenesis and progression of many diseases, such as diabetes, obesity, and cancer. Human GSK-3 has two isoforms, α and β. It is active in resting cells and is inhibited by several hormones such as insulin, endothelial growth factor, and platelet-derived growth factor. Insulin inactivates it by phosphorylation of the specific serine residues Ser21 and Ser9 in GSK-3 isoforms α and β, respectively. In a phosphatidylinositol 3-kinase-dependent way. Glycogen synthase kinase inhibitors are different chemotypes and have variable mechanisms of action; they may be cations, from natural sources, synthetic ATP and non-ATP competitive inhibitors and substrate-competitive inhibitors. GSK3 is a bi-lobar architecture with N-terminal and C-terminal, the N-terminal is responsible for ATP binding and C-terminal which is called as activation loop mediates the kinase activity, Tyrosine located at the C-terminal it essential for full GSK3 activity.
In diabetes, GSK-3β inhibitors increase insulin sensitivity, glycogen synthesis, and glucose metabolism in skeletal muscles, and reduce obesity by affecting the adipogenesis process.[1] GSK-3β is also over expressed in several types of cancers, like colorectal, ovarian, and prostate cancer.[2] GSK-3β inhibitors also aid in the treatment of Alzheimer's disease, stroke, and mood disorders, including bipolar disorder.[3]
Lithium which is used in the treatment of bipolar disorder was the first natural GSK-3 inhibitor discovered. It inhibits GSK-3 directly by competition with magnesium ions and indirectly by phosphorylation and auto-regulation of serine. Lithium has been found to have insulin-like effects on glucose metabolism, including stimulation of glycogen synthesis in fat cells, skin, and muscles, increasing glucose uptake, and activation of GS activity. In addition to inhibition of GSK-3, it also inhibits other enzymes involved in the regulation of glucose metabolisms, such as myo-inositol-1-monophosphatase and 1,6 bisphosphatase. Also, it has shown therapeutic benefit in Alzheimer's and other neurodegenerative diseases such as epileptic neurodegeneration.[4]
Naproxen is a non-steroidal anti-inflammatory drug while cromolyn is an anti-allergic agent which acts as a mast cell stabilizer. Both drugs have demonstrated the anticancer effect in addition to hypoglycemic effect due to inhibition of glycogen synthase kinase-3β (GSK-3β).
To validate the anti-GSK-3β hypothesis of naproxen and cromolyn, docking of the two structures against GSK-3β binding pocket and comparing their fitting with known GSK-3β inhibitor ARA014418 was performed, in addition to measuring the serum glucose, serum insulin, serum C-peptide, weight variation and hepatic glycogen levels for normal and diabetic fasting animal's models to assess their in vitro hypoglycemic effects.
Naproxen and cromolyn were successfully docked into the binding site of GSK-3β (both were fitted into its binding pocket). They exhibited electrostatic, hydrophobic, and hydrogen-bonding interactions with key amino acids within the binding pocket with binding interaction profiles similar to AR-A014418 (the known inhibitor). The negative charges of the carboxylic acid groups in both drugs interact electrostatically with the positively charged guanidine group of Arg141. Moreover, the hydrogen bonding interactions between carboxylic acid moieties of cromolyn and the ammonium groups of Lys183 and Lys60, in addition to π-stacking of the naphthalene ring system of naproxen with the phenolic ring of Tyr134.
Antidiabetic effects of naproxen and cromolyn: In normal animal models, both drugs have showed dose-dependent reduction in blood glucose levels and rise in glycogen levels. In chronic type II diabetic model, glucose levels were also reduced, and glycogen level and insulin levels were elevated in a dose-dependent manner with a reduction in plasma glucose.
Anti-obesity effects of naproxen and cromolyn: Both drugs showed significant anti-obesity effects as they reduce body weight, resistin, and glucose levels in a dose-dependent manner. They were also found to elevate adiponectin, insulin, and C-peptide levels in a dose-dependent manner.[1]
Famotidine is a specific, long-acting H2 antagonist that decreases gastric acid secretion. It is used in the treatment of peptic ulcer disease, GERD, and pathological hypersecretory conditions, like Zollinger–Ellison syndrome. (14,15) H2-receptor antagonists affect hormone metabolism, but their effect on glucose metabolism is not well established. (16) A study has revealed a glucose-lowering effect for famotidine. Recently, a molecular docking was performed as a preliminary in-silico screening test to study famotidine binding to GSK-3β active site.[5]
The study of famotidine binding to the enzyme has showed that famotidine can be docked within the binding pocket of GSK-3β making significant interactions with key points within the GSK-3β binding pocket. Strong hydrogen bond interactions with the key amino acids PRO-136 and VAL -135 and potential hydrophobic interaction with LEU-188 were similar to those found in the ligand binding to the enzyme (AR-A014418).
Furthermore, famotidine showed high GSK-3β binding affinity and inhibitory activity due to interactions that stabilize the complex, namely hydrogen bonding of guanidine group in famotidine with the sulfahydryl moiety in CYS-199; and electrostatic interactions between the same guanidine group with the carboxyl group in ASP-200, the hydrogen bond between the terminal NH2 group, the OH of the TYR-143, and the hydrophobic interaction of the sulfur atom in the thioether with ILE-62. In vitro studies showed that famotidine inhibits GSK-3β activity and increases liver glycogen reserves in a dose dependent manner. A fourfold increase in the liver glycogen level with the use of the highest dose of famotidine (4.4 mg/kg) was observed. Also, famotidine has been shown to decrease serum glucose levels 30, and 60 minutes after oral glucose load in healthy individuals.[6]
Curcumin, which Is a constituent of turmeric spice, has flavoring and coloring properties.[7] It has two symmetrical forms: enol (the most abundant forms) and ketone.[8][9]
Curcumin has wide pharmacological activities: anti-inflammatory,[10] anti-microbial,[11] hypoglycemic, anti-oxidant, and wound healing effects.[12] In animal models with Alzheimer disease, it has anti-destructive effect of beta amyloid in the brain,[13] and recently it shows anti-malarial activity.[14]
Curcumin also has chemo preventative and anti-cancer effects., and it has been shown to attenuate oxidative stress and renal dysfunction in diabetic animals with chronic use.[15]
Curcumin's mechanism of action is anti-inflammatory by inhibiting nuclear transcriptional activator kappa B (NF-KB) that get activated whenever there is inflammatory response.
NF-kB has two regulatory factors, IkB and GSK-3,[16] which suggests curcumin directly binds and inhibits GSK-3B. An in vitro study confirmed GSK-3B inhibition by simulating molecular docking using a silico docking technique.[17] The concentration at which 50% of GK-3B would be inhibited by curcumin is 66.3 nM.[17]
Among its two forms, experimental and theoretical studies show that the enol form is the favored form due to its intra-molecular hydrogen bonding, and an NMR experiment show that enol form exist in a variety of solvents.
Antipsychotic medications were increasingly used for schizophrenia, bipolar disorder, anxiety, and other psychiatric conditions[18] Atypical antipsychotics were more commonly used than first generation antipsychotics because they decrease the risk of extrapyramidal symptoms, such as tardive dyskinesia, and had better efficacy.[19]
Olanzapine and atypical antipsychotics, induce weight gain through increasing body fat.[20] It also distributes glucose metabolism, and several studies shows that it may worsen diabetes.[21]
A recent study shows that olanzapine inhibits GSK3 activity, suggesting olanzapine permits glycogen synthesis. A study conducted on mice to determine the effect of olanzapine on mice blood glucose and glycogen level showed a significant decrease in blood glucose level and elevation of glycogen level in mice, and the IC50% of olanzapine were 91.0 nm which is considered a potent inhibitor. The study also illustrates that sub-chronic use of olanzapine results in potent inhibition of GSK3.[3]
Therefore, according to the previous conclusions that illustrate that olanzapine and other antipsychotics do hyperglycemia, it is still unclear that the drug or the psychiatric illness itself does hyperglycemia.[3]
Pyrimidine analogues are antimetabolites that interfere with nucleic acid synthesis.[22] Some of them have been shown to fit the ATP-binding pocket of GSK-3β to lower blood glucose levels and improve some neuronal diseases.[23]