Among the GSK inhibitors available in market

Among the GSK-3 inhibitors available in market, lithium is probably the only example and the oldest one. Some molecules, both natural and synthetic, such as maleimide derivatives, staurosporine (from the bacterium Streptomyces storosporeus), indole derivatives such as indirubin (used since long in traditional chinese medicine for leukemia), paullone derivatives, pyrazolamide derivatives, pyrimidine derivatives, oxadiazole derivatives, hymenialdisine and many more are in experimental (or clinical trial) stage as inhibitors of GSK-3 [7]. Indirubins (IND) are natural indole derivatives basically extracted from a purple dye from a mollusk Hexaplex trunculus and certain Chinese herbal plants. Indirubin derivatives and analogs have been shown to be potent inhibitors of GSK-3 [8], [9]. Hymenialdisine (HMD) is a molecule derived from a marine sponge such as Agelaside, Halichondriidae, Hymeniasidon aldis and a few more families. HMD has been shown to be potent inhibitor of GSK-3 [7], [10]. LY2090314 is a GSK-3 inhibitor which is currently in oncology trial from Eli Lilly (IN, USA) [11]. Tideglusib is another GSK-3β inhibitor under clinical trial against Alzheiemr’s disease [12], [13]. 6-Bromoindirubin-3-oxime (BIO), a derivative of indirubin, is a very potent inhibitor of GSK-3 [14]. Meridianins, which are brominated 3-(2-aminopyrimidines)-indoles, are naturally found and isolated from Aplidium meridianum (an ascidian, marine invertebrate) [15], [16].
Materials and methods
Results and discussion
Conclusion GSK-3 is an intracellular serine/threonine kinase involved in diversified functions like cellular differentiation, metabolic signaling, neuronal functions, apoptosis and a few others. Its name was derived from its first involvement described in the Meleagrin metabolism where it phosphorylates the target enzyme Glycogen Synthase (GS) and renders it inactive thus preventing the conversion of blood glucose into the glycogen [4]. Later on, it was found to be actively phosphorylating the neuronal target protein Tau, causing it to aggregate intracellularly leading the formation of neurofibrillary tangles (NFTs) [7]. Thus, it was conformed to be an important target against many diseases such as Type 2 Diabetes (NIDDM), Alzheimer’s disease (AD), a few forms of Cancer and other diseases. Deriving ligands against GSK-3 has been in progress for a past few years. People have identified several traditional natural sources such the mollusk H. trunculus (source for indole derivative indirubin), H. aldis which is a source of compounds called hymenialdisine, S. storosporeus, a bacteria which gives staurosporine and several others. Scientists have successfully derived the chemically modified analogs of some of the natural derivatives such as indirubins (6-BIO is one such modified form). Thus, finding molecules which could inhibit the action of GSK-3 would be a great step against several chronic diseases such cancer, AD and NIDDM. A few compounds such as Tideglusib and LY-2090314 are already in clinical trials against Alzheimer’s disease. Keeping these lead molecules as the control, we have compared the docking and ADME properties of a few ligands against our target enzyme, as retrieved from the literature sources. Our analysis, thus, took us to the conclusion that comparison among the ligands tested, 6-bromoindirubin-3-oxime (6-BIO) comes out to be the potent inhibitor of GSK-3. We have come across a few papers that emphasize on a few other derivatives of indirubin such as 7-bromoindirubin-3-oxime (7-BIO) which has a negligible inhibitory activity against GSK-3, unlike 6-BIO, but triggers a considerably fast cell death similar to the one seen in apoptosis. But this function was found to be caspase independent [25]. Thus, the 7-BIO analog could be considered to be a great ligand targeting cancer cells through routes not involving GSK-3.
Acknowledgement
Introduction Consumption of diet rich in saturated fats and refined sugars is associated with development of neurodegenerative diseases, characterized by accumulation of the toxic amyloid beta (Aβ) peptides, chronic inflammation, and neuronal loss [[1], [2], [3]]. Aβ peptides are generated from the amyloid precursor protein (APP) upon cleavage by the proteolytic activities of β- and γ-secretases [4]. APP has been implicated as a regulator of synapse formation, neural plasticity and memory [5,6]. However, overexpression and metabolic processing of APP by β- and γ-secretases generate toxic amyloid peptides (Aβ1–40 and Aβ1–42). Compelling evidence indicates that formation of senile plaques composed of Aβ-peptides can induce neuroimmune response by the immunocompetent glial cells, predominantly astrocytes and microglia. Chronic glial cell activation releases proinflammatory and neurotoxic factors such as tumor necrosis factor (TNF-α), interleukin (IL-6), nitric oxide (NO), cyclooxygenase-2 (COX-2) and reactive oxygen species (ROS) which result in neuronal dysfunction [7].