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Insight into glycogen synthase kinase-3β inhibitory activity of phyto-constituents from Melissa officinalis: in silico studies.

ABSTRACT: Over activity of Glycogen synthase kinase-3β (GSK-3β), a serine/threonine-protein kinase has been implicated in a number of diseases including stroke, type II diabetes and Alzheimer disease (AD). This study aimed to find novel inhibitors of GSK-3β from phyto-constituents of Melissa officinalis with the aid of computational analysis. Molecular docking, induced-fit docking (IFD), calculation of binding free energy via the MM-GBSA approach and Lipinski's rule of five (RO5) were employed to filter the compounds and determine their druggability. Most importantly, the compounds pIC₅₀ were predicted by machine learning-based model generated by AutoQSAR algorithm. The generated model was validated to affirm its predictive model. The best model obtained was Model kpls_desc_38 (R² = 0.8467 and Q² = 0.8069), and this external validated model was utilized to predict the bioactivities of the lead compounds. While a number of characterized compounds from Melissa officinalis showed better docking score, binding free energy alongside adherence to RO5 than co-cystallized ligand, only three compounds (salvianolic acid C, ellagic acid and naringenin) showed more satisfactory pIC₅₀. The results obtained in this study can be useful to design potent inhibitors of GSK-3β.

SUBMITTER: Iwaloye O

PROVIDER: S-EPMC7487069 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Insight into glycogen synthase kinase-3β inhibitory activity of phyto-constituents from <i>Melissa officinalis</i>: in silico studies.

Iwaloye Opeyemi O Elekofehinti Olusola Olalekan OO Oluwarotimi Emmanuel Ayo EA Kikiowo Babatom Iwa BI Fadipe Toyin Mary TM

In silico pharmacology 20200912 1

Over activity of Glycogen synthase kinase-3β (GSK-3β), a serine/threonine-protein kinase has been implicated in a number of diseases including stroke, type II diabetes and Alzheimer disease (AD). This study aimed to find novel inhibitors of GSK-3β from phyto-constituents of <i>Melissa officinalis</i> with the aid of computational analysis. Molecular docking, induced-fit docking (IFD), calculation of binding free energy via the MM-GBSA approach and Lipinski's rule of five (RO5) were employed to f ...[more]

PMID: 32968615

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Project description:Soluble cell adhesion molecules (sCAMs) are secreted ectodomain fragments of surface adhesion molecules, ICAM1 and VCAM1. sCAMs have diverse immune functions beyond their primary function, impacting immune cell recruitment and activation. Elevated sVCAM1 levels have been found to be associated with poor cardiovascular disease (CVD) outcomes, supporting VCAM1's role as a potential diagnostic marker and therapeutic target. Inhibiting sVCAM1's release or its interaction with immune cells could offer cardioprotection in conditions such as diabetes. Membrane-bound surface adhesion molecules are widely expressed in a wide variety of cell types with higher expression in endothelial cells (ECs). Still, the source of sCAMs in the circulation is not clear. Hypothesizing that endothelial cells (ECs) could be a potential source of sCAMs, this study investigated whether dysfunctional EC signaling mechanisms during diabetes cause VCAM1 ectodomain shedding. Our results from samples from an inducible diabetic mouse model revealed increased sVCAM1 plasma levels in diabetes. Protein analysis indicated upregulated VCAM1 expression and metalloproteases ADAM10 and ADAM17 in diabetic ECs. ADAMs are known for proteolytic cleavage of adhesion molecules, contributing to inflammation. GSK3β, implicated in EC VCAM1 expression, was found to be activated in diabetic ECs. GSK3β activation in control ECs increased ADAM10/17 and VCAM1. A GSK3β inhibitor reduced active GSK3β and VCAM1 ectodomain shedding. These findings suggest diabetic ECs with elevated GSK3β activity led to VCAM1 upregulation and ADAM10/17-mediated sVCAM1 shedding. This mechanism underscores the potential therapeutic role of GSK3β inhibition in reducing the levels of circulating sVCAM1. The complex roles of sCAMs extend well beyond CVD. Thus, unraveling the intricate involvement of sCAMs in the initiation and progression of vascular disease, particularly in diabetes, holds significant therapeutic potential.

Dataset Information

Insight into glycogen synthase kinase-3β inhibitory activity of phyto-constituents from Melissa officinalis: in silico studies.

Publications

Insight into glycogen synthase kinase-3β inhibitory activity of phyto-constituents from <i>Melissa officinalis</i>: in silico studies.

Similar Datasets

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