scholarly journals Identification of Novel Glycogen Synthase Kinase-3? Inhibitor through Combined Shape-Based Screening and Molecular Docking Approach

2017 ◽  
Vol 9 (3) ◽  
Author(s):  
Navneet Chauhan ◽  
Anuradha Gajjar ◽  
Rueban Jacob Anicattu Issac ◽  
Sravan Kumar Pucha ◽  
Premkumar Arumugam
Keyword(s):  
Drug Target ◽  
Glycogen Synthase ◽  
Docking Studies ◽  
Glycogen Synthase Kinase ◽  
Kinase Assay ◽  
Glycogen Synthase Kinase 3 ◽  
Therapeutic Drug ◽  
Docking Approach ◽  
Binding Pockets ◽  
Virtual Screening Approach

Glycogen synthase kinase-3? (GSK-3?) is an important class of therapeutic drug target currently receiving wide attention. In our computational approach, shape-based similarity search was used to screen the SPECS database, based on the shape of Tideglusib molecule; a known GSK-3? inhibitor. The resulting virtual hits were applied for docking studies on the known binding pockets of GSK-3?. A novel compound [7,10-dioxo-4,5-dihydro-7H,10H-pyrano[3,2,1-ij]quinolin-8-yl acetate] proposed from docking results in the substrate site of GSK-3? was found to have inhibitory activity (IC50) above 100?M concentration in ADP-GloTM Kinase assay. This communication aims to put forward in identifying newer hit on GSK-3? target via virtual screening approach.

scholarly journals Glycogen Synthase Kinase 3 Is a Potential Drug Target for African Trypanosomiasis Therapy

2008 ◽  
Vol 52 (10) ◽  
pp. 3710-3717 ◽  
Author(s):  
Kayode K. Ojo ◽  
J. Robert Gillespie ◽  
Aaron J. Riechers ◽  
Alberto J. Napuli ◽  
Christophe L. M. J. Verlinde ◽  
...  
Keyword(s):  
Drug Target ◽  
Glycogen Synthase ◽  
Growth Arrest ◽  
Bloodstream Form ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Potential Drug Target ◽  
Potential Drug ◽  
African Trypanosomiasis ◽  
Protein Fusion

ABSTRACT Development of a safe, effective, and inexpensive therapy for African trypanosomiasis is an urgent priority. In this study, we evaluated the validity of Trypanosoma brucei glycogen synthase kinase 3 (GSK-3) as a potential drug target. Interference with the RNA of either of two GSK-3 homologues in bloodstream-form T. brucei parasites led to growth arrest and altered parasite morphology, demonstrating their requirement for cell survival. Since the growth arrest after RNA interference appeared to be more profound for T. brucei GSK-3 “short” (Tb10.161.3140) than for T. brucei GSK-3 “long” (Tb927.7.2420), we focused on T. brucei GSK-3 short for further studies. T. brucei GSK-3 short with an N-terminal maltose-binding protein fusion was cloned, expressed, and purified in a functional form. The potency of a GSK-3-focused inhibitor library against the recombinant enzyme of T. brucei GSK-3 short, as well as bloodstream-form parasites, was evaluated with the aim of determining if compounds that inhibit enzyme activity could also block the parasites' growth and proliferation. Among the compounds active against the cell, there was an excellent correlation between activity inhibiting the T. brucei GSK-3 short enzyme and the inhibition of T. brucei growth. Thus, there is reasonable genetic and chemical validation of GSK-3 short as a drug target for T. brucei. Finally, selective inhibition may be required for therapy targeting the GSK-3 enzyme, and a molecular model of the T. brucei GSK-3 short enzyme suggests that compounds that selectively inhibit T. brucei GSK-3 short over the human GSK-3 enzymes can be found.

scholarly journals In silico analysis of Glycogen synthase kinase 3-beta (GSK-3β) as aflatoxin binder

2019 ◽  
Vol 12 (3) ◽  
pp. 1449-1456
Keyword(s):  
Glycogen Synthase ◽  
In Silico Analysis ◽  
Docking Studies ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Lipinski’S Rule ◽  
Lipinski’S Rule Of Five ◽  
Aspergillus Nomius ◽  
Gsk 3Β ◽  
Silico Analysis

Aflatoxins are secondary metabolites of certain fungi like Aspergillus flavus, Aspergillus niger, Aspergillus nomius and Aspergillus parasiticus. Food products like cereals, milk, milk products, nuts, oilseeds and spices are reported for aflatoxins contamination. Among the fourteen aflatoxin types reported so far, aflatoxins B1, B2, G1, G2, M1, and M2 are commonly studied. Aflatoxins are known to cause various diseases including aflatoxicosis in livestock and domestic animals and cancer in humans. Recently aflatoxin B1 has reported binding with Glycogen synthase kinase 3-beta (GSK-3β). This prompted to carry out the present study, where Glycogen synthase kinase 3-beta (GSK-3β) was evaluated on the docking behaviour of 13 aflatoxin analogues using Patch Dock. In addition, molecular physicochemical, drug-likeness, ADME (Absorption, Distribution, Metabolism and Excretion analyses) were also carried out. The molecular physiochemical analysis revealed that aflatoxin analogue showed nil violation and complied well with the Lipinski’s rule of five. ADME analysis indicates all thirteen aflatoxin analogue predicated to have high gastro-intestine (GI) absorption property. Docking studies, with GSK-3β, revealed that aflatoxin G2 analogue showed the largest atomic contact energy (-224.82 kcal/mol) and Aflatoxin P1 analogue had the least (-160.33 kcal/mol). In addition, aflatoxin P1 analogue has interacted with Asp200 amino acid residue of GSK-3β. Thus, the present study showed the potential of GSK-3β as aflatoxin binder.

Glycogen synthase kinase 3: a drug target for CNS therapies

2004 ◽  
Vol 89 (6) ◽  
pp. 1313-1317 ◽  
Author(s):  
Ratan V. Bhat ◽  
Samantha L. Budd Haeberlein ◽  
Jesús Avila
Keyword(s):  
Drug Target ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3
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