Exploring the mechanistic insights of Cas scaffolding protein family member 4 with protein tyrosine kinase 2 in Alzheimer’s disease by evaluating protein interactions through molecular docking and dynamic simulations

Hassan, Mubashir; Shahzadi, Saba; Alashwal, Hany; Zaki, Nazar; Moustafa, Ahmed A.

doi:10.1007/s10072-018-3430-2

Cited by 10 publications

(7 citation statements)

References 79 publications

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“…It is notable that the most enriched terms include the regulation of neuron projection development, vesicle localization, establishment of vesicle localization, cotranslational protein targeting to membrane, and protein targeting to endoplasmic reticulum (ER). These results indicated that the alteration of neurofunction [29], protein localization [30], and ER signal transduction [30] possibly participates in the development of AD. The enriched terms related to neurofunction are consistent with the feature of AD as a neurodegenerative disease.…”

Section: Discussionmentioning

confidence: 99%

A 3-Gene-Based Diagnostic Signature in Alzheimer’s Disease

et al. 2021

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Background: Alzheimer’s disease (AD) is a chronic neurodegenerative disease. In this study, potential diagnostic biomarkers were identified for AD. Methods: All AD samples and healthy samples were collected from 2 datasets in the GEO database, in which differentially expressed genes (DEGs) were analyzed by using the limma package of R language. GO and KEGG pathway enrichment was conducted basing on the DEGs via the clusterProfiler package of R. And, the PPI network construction and gene prediction were performed using the STRING database and Cytoscape. Then, a logistic regression model was constructed to predict the sample type. Results: Bioinformatic analysis of GEO datasets revealed 2,063 and 108 DEGs in GSE5281 and GSE4226 datasets, separately, and 15 overlapping DEGs were found. GO and KEGG enrichment analysis revealed terms associated with neurodevelopment. Then, we built a logistic regression model based on the hub genes from the PPI network and optimized the model to 3 genes (ALDOA, ENC1, and NFKBIA). The values of area under the curve of the training set GSE5281 and testing set GSE4226 were 0.9647 and 0.7857, respectively, which implied the efficacy of this model. Conclusion: The comprehensive bioinformatic analysis of gene expression in AD patients and the effective logistic regression model built in our study may provide promising research value for diagnostic methods of AD.

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Section: Discussionmentioning

confidence: 99%

A 3-Gene-Based Diagnostic Signature in Alzheimer’s Disease

et al. 2021

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“…Molecular docking is a computational approach used to predict the binding conformational behavior of biomolecules, i.e., drugs and proteins. − All of the screened drugs were docked and analyzed based on binding affinity (kcal/mol) (see the Supplementary Data S2). From docking results, it has been observed that from 100 FDA-approved drugs, 24 drugs showed binding affinity values higher than −7 kcal/mol and may have good binding potential inside the binding pocket of the EWS protein.…”

Section: Results and Discussionmentioning

confidence: 99%

Exploration of Potential Ewing Sarcoma Drugs from FDA-Approved Pharmaceuticals through Computational Drug Repositioning, Pharmacogenomics, Molecular Docking, and MD Simulation Studies

et al. 2022

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Novel drug development is a time-consuming process with relatively high debilitating costs. To overcome this problem, computational drug repositioning approaches are being used to predict the possible therapeutic scaffolds against different diseases. In the current study, computational drug repositioning approaches were employed to fetch the promising drugs from the pool of FDA-approved drugs against Ewing sarcoma. The binding interaction patterns and conformational behaviors of screened drugs within the active region of Ewing sarcoma protein (EWS) were confirmed through molecular docking profiles. Furthermore, pharmacogenomics analysis was employed to check the possible associations of selected drugs with Ewing sarcoma genes. Moreover, the stability behavior of selected docked complexes (drugs-EWS) was checked by molecular dynamics simulations. Taken together, astemizole, sulfinpyrazone, and pranlukast exhibited a result comparable to pazopanib and can be used as a possible therapeutic agent in the treatment of Ewing sarcoma.

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“…Protein interactions initiate the downstream signaling pathways and are involved in the occurance of neurological diseases 57 , 58 . The decreased flexibility of protein backbone is considered a major hallmark for checking the stability of docked complexes using MD simulation 56 .…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis

Hassan

Zahid

Alashwal

et al. 2021

Sci Rep

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Proteins are tiny players involved in the activation and deactivation of multiple signaling cascades through interactions in cells. The TNFR1 and MADD interact with each other and mediate downstream protein signaling pathways which cause neuronal cell death and Alzheimer’s disease. In the current study, a molecular docking approach was employed to explore the interactive behavior of TNFR1 and MADD proteins and their role in the activation of downstream signaling pathways. The computational sequential and structural conformational results revealed that Asp400, Arg58, Arg59 were common residues of TNFR1 and MADD which are involved in the activation of downstream signaling pathways. Aspartic acid in negatively charged residues is involved in the biosynthesis of protein. However, arginine is a positively charged residue with the potential to interact with oppositely charged amino acids. Furthermore, our molecular dynamic simulation results also ensured the stability of the backbone of TNFR1 and MADD death domains (DDs) in binding interactions. This DDs interaction mediates some conformational changes in TNFR1 which leads to the activation of mediators proteins in the cellular signaling pathways. Taken together, a better understanding of TNFR1 and MADD receptors and their activated signaling cascade may help treat Alzheimer’s disease. The death domains of TNFR1 and MADD could be used as a novel pharmacological target for the treatment of Alzheimer’s disease by inhibiting the MAPK pathway.

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Exploring the mechanistic insights of Cas scaffolding protein family member 4 with protein tyrosine kinase 2 in Alzheimer’s disease by evaluating protein interactions through molecular docking and dynamic simulations

Cited by 10 publications

References 79 publications

A 3-Gene-Based Diagnostic Signature in Alzheimer’s Disease

A 3-Gene-Based Diagnostic Signature in Alzheimer’s Disease

Exploration of Potential Ewing Sarcoma Drugs from FDA-Approved Pharmaceuticals through Computational Drug Repositioning, Pharmacogenomics, Molecular Docking, and MD Simulation Studies

Mechanistic insights into TNFR1/MADD death domains in Alzheimer’s disease through conformational molecular dynamic analysis

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