Designing of dual inhibitors for GSK-3β and CDK5: Virtual screening and<i>in vitro</i>biological activities study

Xie, Hongbo; Wen, Haixia; Zhang, Denan; Liu, Lei; Liu, Bo; Liu, Qiuqi; Jin, Qing; Ke, Kehui; Hu, Ming; Chen, Xiujie

doi:10.18632/oncotarget.15085

Cited by 25 publications

(18 citation statements)

References 38 publications

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“…Interestingly, the efficacy of various antiepileptic drugs (AEDs) has been tested in epilepsy experimental models and in AD patients, showing a promising function in cognitive impairment prevention (Sánchez et al, 2018). Since tau hyperphosphorylation is the main mechanism responsible for NFT formation, it has been suggested that inhibiting different tau kinases such as CDK5 and GSK3β, involved in tau hyperphosphorylation, could reduce their aggregation (Xie et al, 2017;Holzer et al, 2018), observed in AD (Morris et al, 2011) and epilepsy (Sen et al, 2007;Thom et al, 2011;Tai et al, 2016).…”

Section: Therapeuticsmentioning

confidence: 99%

GSK3β and Tau Protein in Alzheimer’s Disease and Epilepsy

Toral-Ríos

Pichardo-Rojas

Alonso-Vanegas

et al. 2020

Front. Cell. Neurosci.

113

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Alzheimer's disease (AD) is the most common form of dementia present in older adults; its etiology involves genetic and environmental factors. In recent years, epidemiological studies have shown a correlation between AD and chronic epilepsy since a considerable number of patients with AD may present seizures later on. Although the pathophysiology of seizures in AD is not completely understood, it could represent the result of several molecular mechanisms linked to amyloid beta-peptide (Aβ) accumulation and the hyperphosphorylation of tau protein, which may induce an imbalance in the release and recapture of excitatory and inhibitory neurotransmitters, structural alterations of the neuronal cytoskeleton, synaptic loss, and neuroinflammation. These changes could favor the recurrent development of hypersynchronous discharges and epileptogenesis, which, in a chronic state, favor the neurodegenerative process and influence the cognitive decline observed in AD. Supporting this correlation, histopathological studies in the brain tissue of temporal lobe epilepsy (TLE) patients have revealed the presence of Aβ deposits and the accumulation of tau protein in the neurofibrillary tangles (NFTs), accompanied by an increase of glycogen synthase kinase-3 beta (GSK3β) activity that may lead to an imminent alteration in posttranslational modifications of some microtubule-associated proteins (MAPs), mainly tau. The present review is focused on understanding the pathological aspects of GSK3β and tau in the development of TLE and AD.

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Section: Therapeuticsmentioning

confidence: 99%

GSK3β and Tau Protein in Alzheimer’s Disease and Epilepsy

Toral-Ríos

Pichardo-Rojas

Alonso-Vanegas

et al. 2020

Front. Cell. Neurosci.

113

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“…Recent studies utilized VS for AD drug screening for MTDLs that are intended to inhibit multiple associated targets. In this regard, two significant targets-GSK-3β and CDK5-were inhibited by means of sequential docking to screen compounds, whereas ligand-based virtual screening was performed in another study on inhibition of GSK-3β and BACE1 [190,191]. Nonetheless, recursive partitioning (RP) and NB, ML-based VS methods were used to screen compounds for MTDLs against AD.…”

Section: Ai-based Interventions In Advanced Therapeuticsmentioning

confidence: 99%

The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

Pirzada

Javaid

Choi

2020

Genes

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Inflammasomes are intracellular multiprotein complexes in the cytoplasm that regulate inflammation activation in the innate immune system in response to pathogens and to host self-derived molecules. Recent advances greatly improved our understanding of the activation of nucleotide-binding oligomerization domain-like receptor (NLR) family pyrin domain containing 3 (NLRP3) inflammasomes at the molecular level. The NLRP3 belongs to the subfamily of NLRP which activates caspase 1, thus causing the production of proinflammatory cytokines (interleukin 1β and interleukin 18) and pyroptosis. This inflammasome is involved in multiple neurodegenerative and metabolic disorders including Alzheimer's disease, multiple sclerosis, type 2 diabetes mellitus, and gout. Therefore, therapeutic targeting to the NLRP3 inflammasome complex is a promising way to treat these diseases. Recent research advances paved the way toward drug research and development using a variety of machine learning-based and artificial intelligence-based approaches. These state-of-the-art approaches will lead to the discovery of better drugs after the training of such a system.

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“…There exist numerous examples in the literature of the application of various types of machine learning classifiers for virtual screening [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Commonly used classifiers include naïve Bayes, k-nearest neighbors, support vector machines, random forests, and artificial neural networks (ANNs).…”

Section: Introductionmentioning

confidence: 99%

A Pilot Study of Multi-Input Recurrent Neural Networks for Drug-Kinase Binding Prediction

2020

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The use of virtual drug screening can be beneficial to research teams, enabling them to narrow down potentially useful compounds for further study. A variety of virtual screening methods have been developed, typically with machine learning classifiers at the center of their design. In the present study, we created a virtual screener for protein kinase inhibitors. Experimental compound–target interaction data were obtained from the IDG-DREAM Drug-Kinase Binding Prediction Challenge. These data were converted and fed as inputs into two multi-input recurrent neural networks (RNNs). The first network utilized data encoded in one-hot representation, while the other incorporated embedding layers. The models were developed in Python, and were designed to output the IC50 of the target compounds. The performance of the models was assessed primarily through analysis of the Q2 values produced from runs of differing sample and epoch size; recorded loss values were also reported and graphed. The performance of the models was limited, though multiple changes are proposed for potential improvement of a multi-input recurrent neural network-based screening tool.

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Designing of dual inhibitors for GSK-3β and CDK5: Virtual screening andin vitrobiological activities study

Cited by 25 publications

References 38 publications

GSK3β and Tau Protein in Alzheimer’s Disease and Epilepsy

GSK3β and Tau Protein in Alzheimer’s Disease and Epilepsy

The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

A Pilot Study of Multi-Input Recurrent Neural Networks for Drug-Kinase Binding Prediction

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