scholarly journals ENERGY-BASED PHARMACOPHORE MODELING, VIRTUAL SCREENING, AND MOLECULAR DYNAMICS TO IDENTIFY POTENTIAL INHIBITORS FOR GLYCOGEN SYNTHASE KINASE 3 BETA

2018 ◽  
Vol 11 (2) ◽  
pp. 181
Author(s):  
Sheema Jb ◽  
Waheeta Hopper
Keyword(s):  
Molecular Dynamics ◽  
Wound Healing ◽  
Glycogen Synthase ◽  
Pharmacophore Model ◽  
Pharmacophore Modeling ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Systemic Side Effects ◽  
The Stability ◽  
Potential Inhibitors

  Objective: Glycogen synthase kinase 3 beta (GSK3β) is one of the main targets for wound healing activity. Our objective is to identify novel inhibitors for GSK3β using in silico approach.Methods: Grid-based molecular docking, energy-based pharmacophore (e-pharmacophore) modeling, and molecular dynamics (MD) studies were performed for phytocompounds with GSK3β and compared with standard drugs using Schrodinger software.Results: The glide scores and the molecular interactions of the phytocompounds were well comparable to the standard drugs. The MD was performed for the target bound to the best scoring ligand, entagenic acid. The pharmacophore features of this docked complex were modeled as e-pharmacophore. The constructed e-pharmacophore model was screened against phytocompounds retrieved from literature to identify the ligands with similar pharmacophore features.Conclusion: The glide scores of fukinolic acid, cimicifugic acid, and linarin were −10.99, −8.28, and −7.25 kcal/mol, respectively. The further 50 nanoseconds MD study determined the stability of GSK3β-linarin complex. Nitrofurazone and sulfathiazole drugs can lead to systemic side effects. Hence, it is concluded that linarin could be a potent wound healing compound against GSK3β.

scholarly journals Glycogen Synthase Kinase 3 Phosphorylates RBL2/p130 during Quiescence

2004 ◽  
Vol 24 (20) ◽  
pp. 8970-8980 ◽  
Author(s):  
Larisa Litovchick ◽  
Anton Chestukhin ◽  
James A. DeCaprio
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Growth Factor Signaling ◽  
Cycle Progression ◽  
Pocket Proteins ◽  
Cyclin Dependent Kinases ◽  
The Stability

ABSTRACT Phosphorylation of the retinoblastoma-related or pocket proteins RB1/pRb, RBL1/p107, and RBL2/p130 regulates cell cycle progression and exit. While all pocket proteins are phosphorylated by cyclin-dependent kinases (CDKs) during the G1/S-phase transition, p130 is also specifically phosphorylated in G0-arrested cells. We have previously identified several phosphorylated residues that match the consensus site for glycogen synthase kinase 3 (GSK3) in the G0 form of p130. Using small-molecule inhibitors of GSK3, site-specific mutants of p130, and phospho-specific antibodies, we demonstrate here that GSK3 phosphorylates p130 during G0. Phosphorylation of p130 by GSK3 contributes to the stability of p130 but does not affect its ability to interact with E2F4 or cyclins. Regulation of p130 by GSK3 provides a novel link between growth factor signaling and regulation of the cell cycle progression and exit.

scholarly journals Yeast Glycogen Synthase Kinase 3 Is Involved in Protein Degradation in Cooperation with Bul1, Bul2, and Rsp5

2000 ◽  
Vol 20 (18) ◽  
pp. 6712-6720 ◽  
Author(s):  
Tomoko Andoh ◽  
Yuzoh Hirata ◽  
Akira Kikuchi
Keyword(s):  
Protein Degradation ◽  
Temperature Sensitivity ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Null Mutant ◽  
Osmotic Stabilizer ◽  
Multiple Copies ◽  
Gsk 3Β ◽  
The Stability

ABSTRACT The yeast Saccharomyces cerevisiae has four genes,MCK1, MDS1 (RIM11),MRK1, and YOL128c, that encode glycogen synthase kinase 3 (GSK-3) homologs. The gsk-3 null mutant, in which these four genes are disrupted, shows temperature sensitivity, which is suppressed by the expression of mammalian GSK-3β and by an osmotic stabilizer. Suppression of temperature sensitivity by an osmotic stabilizer is also observed in the bul1 bul2 double null mutant, and the temperature sensitivity of the bul1 bul2 double null mutant is suppressed by multiple copies ofMCK1. We have screened rog mutants (revertants of gsk-3) which suppress the temperature sensitivity of themck1 mds1 double null mutant and found that two of them,rog1 and rog2, also suppress the temperature sensitivity of the bul1 bul2 double null mutant. Bul1 and Bul2 have been reported to bind to Rsp5, a hect (for homologous to E6-associated-protein carboxyl terminus)-type ubiquitin ligase, but involvement of Bul1 and Bul2 in protein degradation has not been demonstrated. We find that Rog1, but not Rog2, is stabilized in thegsk-3 null and the bul1 bul2 double null mutants. Rog1 binds directly to Rsp5, and their interaction is dependent on GSK-3. Furthermore, Rog1 is stabilized in thenpi1 mutant, in which RSP5 expression levels are reduced. These results suggest that yeast GSK-3 regulates the stability of Rog1 in cooperation with Bul1, Bul2, and Rsp5.

scholarly journals Pharmacophore Modeling, Docking, and Molecular Dynamics Simulation of Flavonoids as Inhibitors of Urokinase-type Plasminogen Activator

2022 ◽  
Vol 53 (3) ◽  
pp. 451-465
Author(s):  
Daryono Hadi Tjahjono ◽  
Bina Lohita Sari ◽  
Slamet Ibrahim
Keyword(s):  
Molecular Dynamics ◽  
Binding Energy ◽  
Plasminogen Activator ◽  
Pharmacophore Model ◽  
In Silico Analysis ◽  
Pharmacophore Modeling ◽  
Dynamics Simulation ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
The Stability

The urokinase-type plasminogen activator (uPA) system plays a significant role in the invasion and metastasis of cancer cells. The present study was conducted to investigate natural product compounds as inhibitors and hit molecules of uPA using in-silico analysis. A pharmacophore model was built to screen the Indonesian Herbal Database (HerbalDB) to obtain inhibitors of different scaffolds. Based on the molecular docking score, four ligands were selected as potential uPA inhibitors. Subsequently, the stability of the ligand-uPA complex was analyzed using molecular dynamics (MD) simulation. An RMSD graph of the backbone protein and the RMSF values of the amino acid residues were also determined. In addition, the MM-PBSA method was applied to calculate the free binding energy. According to the results, Model_3, characterized by aromatic rings 23 (F1 and F2), cationic H-bond donor (F3), and metal ligator (F4) features, had an adequate goodness-of-hit score (GH). The four top-ranked ligands, isorhamnetin, rhamnetin, quercetin, and kaempferol, showed higher docking scores compared to the others. This study confirmed that isorhamnetin, rhamnetin, and kaempferol build stable complexes with uPA with lower binding energy than quercetin.

Wound healing activity and docking of glycogen-synthase-kinase-3-β-protein with isolated triterpenoid lupeol in rats

Phytomedicine ◽  
2008 ◽  
Vol 15 (9) ◽  
pp. 763-767 ◽  
Author(s):  
B.G. Harish ◽  
V. Krishna ◽  
H.S. Santosh Kumar ◽  
B.M. Khadeer Ahamed ◽  
R. Sharath ◽  
...  
Keyword(s):  
Wound Healing ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Β Protein ◽  
Wound Healing Activity
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