Evaluation of selected carotenoids of Lycopersicon esculentum variants as therapeutic targets for ‘Alzheimer’s disease: an in silico approach

AbstractThe seriousness and menace of the worldwide weight of ‘Alzheimer’s disease have been related to a few factors, which incorporate antioxidant system depletion, mutation of proteins, and high expression of cholinesterases due to aging, environmental influence, diet, infectious agents, and hormonal imbalance. Overexpression of cholinesterases has been emphatically connected to ‘Alzheimer’s disease because of the unreasonable hydrolysis of acetylcholine and butyrylcholine. Certain plant phytochemicals, for example, beta-carotenoids, lutein, neoxanthin, and viola-xanthine from Lycopersicon esculentum Mill. Var. esculentum (ESC) and Lycopersicon esculentum Mill. Var. cerasiforme (CER) has been utilized altogether as a therapeutic candidate for the treatment of ‘Alzheimer’s disease. Therefore, this research sought to investigate the drug-likeness of the individual carotenoids as detailed for cholinesterase inhibition in the treatment of ‘Alzheimer’s disease. Four potential cholinesterase inhibitors from ESC and CER were retrieved from the PubChem database. Investigation of their drug-likeness, toxicity prediction, molecular docking, and dynamic simulations were carried out using Molinspiration, PreADMET V.2.0, Patchdock server, and Schrodinger Maestro software respectively. Neoxanthin was ranked the safest with a greater tendency to inhibit the cholinesterases with high binding affinity. In addition, its stability after simulation in a mimicked biological environment suggests its relevance as a potential drug candidate for the treatment of ‘Alzheimer’s disease through the inhibition of cholinesterases.

Download Full-text

Implications of Some Selected Flavonoids Towards Alzheimer’s Disease with the Emphasis on Cholinesterase Inhibition and their Bioproduction by Metabolic Engineering

Current Pharmaceutical Biotechnology ◽

10.2174/1389201015666140813123204 ◽

2014 ◽

Vol 15 (4) ◽

pp. 352-361 ◽

Cited By ~ 7

Author(s):

Ilkay Orhan

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Metabolic Engineering ◽

Cholinesterase Inhibition

Download Full-text

High-throughput screening of natural compounds and inhibition of a major therapeutic target HsGSK-3β for Alzheimer’s disease using computational approaches

Journal of Genetic Engineering and Biotechnology ◽

10.1186/s43141-021-00163-w ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Rohit Shukla ◽

Tiratha Raj Singh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Throughput Screening ◽

Complex Disease ◽

Glycogen Synthase ◽

Binding Free Energy ◽

Drug Candidate ◽

Pharmacokinetic Analysis ◽

Pharmacokinetic Parameters ◽

Computational Approaches

Abstract Background Alzheimer’s disease is a leading neurodegenerative disease worldwide and is the 6th leading cause of death in the USA. AD is a very complex disease and the drugs available in the market cannot fully cure it. The glycogen synthase kinase 3 beta plays a major role in the hyperphosphorylation of tau protein which forms the neurofibrillary tangles which is a major hallmark of AD. In this study, we have used a series of computational approaches to find novel inhibitors against GSK-3β to reduce the TAU hyperphosphorylation. Results We have retrieved a set of compounds (n=167,741) and screened against GSK-3β in four sequential steps. The resulting analysis of virtual screening suggested that 404 compounds show good binding affinity and can be employed for pharmacokinetic analysis. From here, we have selected 20 compounds those were good in terms of pharmacokinetic parameters. All these compounds were re-docked by using Autodock Vina followed by Autodock. Four best compounds were employed for MDS and here predicted RMSD, RMSF, Rg, hydrogen bonds, SASA, PCA, and binding-free energy. From all these analyses, we have concluded that out of 167,741 compounds, the ZINC15968620, ZINC15968622, and ZINC70707119 can act as lead compounds against HsGSK-3β to reduce the hyperphosphorylation. Conclusion The study suggested three compounds (ZINC15968620, ZINC15968622, and ZINC70707119) have great potential to be a drug candidate and can be tested using in vitro and in vivo experiments for further characterization and applications.

Download Full-text

A novel orally active HDAC6 inhibitor T-518 shows a therapeutic potential for Alzheimer’s disease and tauopathy in mice

Scientific Reports ◽

10.1038/s41598-021-94923-w ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tomohiro Onishi ◽

Ryouta Maeda ◽

Michiko Terada ◽

Sho Sato ◽

Takahiro Fujii ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Drug Candidate ◽

Histone Deacetylase 6 ◽

Cellular Assays ◽

Age Related ◽

Acetylation State ◽

Hdac6 Inhibitor ◽

Orally Active

AbstractAccumulation of tau protein is a key pathology of age-related neurodegenerative diseases such as Alzheimer's disease and progressive supranuclear palsy. Those diseases are collectively termed tauopathies. Tau pathology is associated with axonal degeneration because tau binds to microtubules (MTs), a component of axon and regulates their stability. The acetylation state of MTs contributes to stability and histone deacetylase 6 (HDAC6) is a major regulator of MT acetylation status, suggesting that pharmacological HDAC6 inhibition could improve axonal function and may slow the progression of tauopathy. Here we characterize N-[(1R,2R)-2-{3-[5-(difluoromethyl)-1,3,4-oxadiazol-2-yl]-5-oxo-5H,6H,7H-pyrrolo[3,4-b]pyridin-6-yl}cyclohexyl]-2,2,3,3,3-pentafluoropropanamide (T-518), a novel, potent, highly selective HDAC6 inhibitor with clinically favorable pharmacodynamics. T-518 shows potent inhibitory activity against HDAC6 and superior selectivity over other HDACs compared with the known HDAC6 inhibitors in the enzyme and cellular assays. T-518 showed brain penetration in an oral dose and blocked HDAC6-dependent tubulin deacetylation at Lys40 in mouse hippocampus. A 2-week treatment restored impaired axonal transport and novel object recognition in the P301S tau Tg mouse, tauopathy model, while a 3-month treatment also decreased RIPA-insoluble tau accumulation. Pharmaceutical inhibition of HDAC6 is a potential therapeutic strategy for tauopathy, and T-518 is a particularly promising drug candidate.

Download Full-text

The individual course of neuropsychiatric symptoms in people with Alzheimer's and Lewy body dementia: 12-year longitudinal cohort study

The British Journal of Psychiatry ◽

10.1192/bjp.2019.195 ◽

2019 ◽

Vol 216 (1) ◽

pp. 43-48 ◽

Cited By ~ 9

Author(s):

Audun Osland Vik-Mo ◽

Lasse Melvaer Giil ◽

Miguel Germán Borda ◽

Clive Ballard ◽

Dag Aarsland

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Neuropsychiatric Symptoms ◽

Personalised Medicine ◽

Lewy Bodies ◽

Lewy Body Dementia ◽

Psychotic Symptoms ◽

Primary Inclusion ◽

The Individual

IntroductionUnderstanding the natural course of neuropsychiatric symptoms (NPS) in dementia is important for planning patient care and trial design, but few studies have described the long-term course of NPS in individuals.MethodPrimary inclusion of 223 patients with suspected mild dementia from general practice were followed by annual assessment, including the Neuropsychiatric Inventory (NPI), for up to 12 years. Total and item NPI scores were classified as stable, relapsing, single episodic or not present based on 4.96 (s.d. 2.3) observations (98% completeness of longitudinal data) for 113 patients with Alzheimer's disease and 84 patients with LBD (68 dementia with Lewy bodies and 16 Parkinson's disease dementia).ResultsWe found that 80% had stable NPI total ≥1, 50% had stable modest NPI total ≥12 and 25% had stable NPI total ≥24 scores. Very severe NPS (≥48) were mostly single episodes, but 8% of patients with Alzheimer's disease had stable severe NPS. Patients with Alzheimer's disease and the highest 20% NPI total scores had a more stable or relapsing course of four key symptoms: aberrant motor behaviour, aggression/agitation, delusions and irritability (odds ratio 55, P < 0.001). This was not seen in LBD. Finally, 57% of patients with Alzheimer's disease and 84% of patients with LBD had reoccurring psychotic symptoms.ConclusionsWe observed a highly individual course of NPS, with most presenting as a single episode or relapsing; a stable course was less common, especially in LBD. These findings demonstrate the importance of an individualised approach (i.e. personalised medicine) in dementia care.

Download Full-text