scholarly journals Multitarget Approach to Drug Candidates against Alzheimer’s Disease Related to AChE, SERT, BACE1 and GSK3β Protein Targets

Molecules ◽  
2020 ◽  
Vol 25 (8) ◽  
pp. 1846
Author(s):  
Larisa Ivanova ◽  
Mati Karelson ◽  
Dimitar A. Dobchev
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Experimental Testing ◽  
Drug Candidate ◽  
Multilinear Regression ◽  
Protein Targets ◽  
Drug Candidates ◽  
Multifunctional Compounds ◽  
Contemporary Medicine ◽  
Effective Drugs

Alzheimer’s disease is a neurodegenerative condition for which currently there are no drugs that can cure its devastating impact on human brain function. Although there are therapeutics that are being used in contemporary medicine for treatment against Alzheimer’s disease, new and more effective drugs are in great demand. In this work, we proposed three potential drug candidates which may act as multifunctional compounds simultaneously toward AChE, SERT, BACE1 and GSK3β protein targets. These candidates were discovered by using state-of-the-art methods as molecular calculations (molecular docking and molecular dynamics), artificial neural networks and multilinear regression models. These methods were used for virtual screening of the publicly available library containing more than twenty thousand compounds. The experimental testing enabled us to confirm a multitarget drug candidate active at low micromolar concentrations against two targets, e.g., AChE and BACE1.

scholarly journals Potential Therapeutic Strategies for Alzheimer’s Disease Targeting or Beyondβ-Amyloid: Insights from Clinical Trials

2014 ◽  
Vol 2014 ◽  
pp. 1-22 ◽  
Author(s):  
Qiutian Jia ◽  
Yulin Deng ◽  
Hong Qing
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Drug Targets ◽  
Neurodegenerative Disorder ◽  
Therapeutic Strategies ◽  
Therapeutic Approaches ◽  
Drug Candidates ◽  
Effective Drugs ◽  
Novel Drug

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with two hallmarks:β-amyloid plagues and neurofibrillary tangles. It is one of the most alarming illnesses to elderly people. No effective drugs and therapies have been developed, while mechanism-based explorations of therapeutic approaches have been intensively investigated. Outcomes of clinical trials suggested several pitfalls in the choice of biomarkers, development of drug candidates, and interaction of drug-targeted molecules; however, they also aroused concerns on the potential deficiency in our understanding of pathogenesis of AD, and ultimately stimulated the advent of novel drug targets tests. The anticipated increase of AD patients in next few decades makes development of better therapy an urgent issue. Here we attempt to summarize and compare putative therapeutic strategies that have completed clinical trials or are currently being tested from various perspectives to provide insights for treatments of Alzheimer’s disease.

Tackling Alzheimer’s Disease with Existing Drugs: Playing Dirty for Bypassing Obstacles

2020 ◽  
Vol 27 ◽  
Author(s):  
Angela Rampa ◽  
Silvia Gobbi ◽  
Federica Belluti ◽  
Alessandra Bisi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Unmet Need ◽  
Drug Repurposing ◽  
Development Programs ◽  
Disease Pathogenesis ◽  
Structural Modifications ◽  
Beneficial Effects ◽  
Multifunctional Compounds ◽  
Effective Drugs

: The unmet need for the development of effective drugs to treat Alzheimer's disease has been steadily growing, representing a major challenge in drug discovery. In this context, drug repurposing, namely the identification of novel therapeutic indications for approved or investigational compounds, can be seen as an attractive attempt to obtain new medications reducing both the time and the economic burden usually required for research and development programs. In the last years, several classes of drugs have evidenced promising beneficial effects in neurodegenerative diseases, and for some of them preliminary clinical trials have been started. This review aims to illustrate some of the most recent examples of drugs reprofiled for Alzheimer’s disease, considering not only the finding of new uses for existing drugs, but also the new hypotheses on disease pathogenesis, that could promote previously unconsidered therapeutic regimens. Moreover, some examples of structural modifications performed on existing drugs in order to obtain multifunctional compounds will also be described.

Multi-Target Directed Drugs as a Modern Approach for Drug Design Towards Alzheimer’s Disease: An Update

2018 ◽  
Vol 25 (29) ◽  
pp. 3491-3525 ◽  
Author(s):  
Matheus de Freitas Silva ◽  
Kris Simone Tranches Dias ◽  
Vanessa Silva Gontijo ◽  
Cindy Juliet Cristancho Ortiz ◽  
Claudio Viegas
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Neurodegenerative Disorder ◽  
Drug Candidate ◽  
Modern Approach ◽  
Biological Targets ◽  
Drug Candidates ◽  
Multiple Factors ◽  
Recent Approach

Alzheimer’s disease (AD) is a progressive multifactorial neurodegenerative disorder. Currently, no effective treatment is available and this is due to multiple factors involved in pathophysiology and severity of AD. A recent approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDL) strategy, has been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets. The discovery of drug candidates capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. This review is a complement to another review article, recently published by our group, which covered the previous period of 2005-2012, and highlights recent advances and examples of the exploitation of MTDLs approach in the rational design of novel drug candidate prototypes for the treatment of AD.

scholarly journals An overview of pharmacological activities of acridine derivatives

2020 ◽  
Vol 11 (4) ◽  
pp. 6922-6931
Author(s):  
Magesh M ◽  
Gandhimathi R
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Biological Activities ◽  
Drug Regimen ◽  
Spreading Rate ◽  
Tumour Cells ◽  
Drug Candidate ◽  
Drug Candidates ◽  
Drug Molecules ◽  
Wide Range

The derivatives of acridine can be served as a lead molecule of an antibacterial, anti-viral antiprotozoal, anti-viral, antitubercular, anti-fungal, anti-malarial and anti-cancer agents. Even though the usage of acridine becomes limited due to its side effects, so many potent and safe compounds can be derived through molecular modification in the acridine ring. Since the resistance of pathogens and tumour cells has become more common nowadays, it necessitates the search of new drug candidates. Since the treatment and management of Alzheimer's disease is such a complicated and proper drug regimen is not designed so far, The cholinesterase activity of acridines can be used to derive novel compounds from treating Alzheimer's disease. The mosquito larvicidal activity of acridines is considered as an advantage as vector control to reduce the spreading rate of malaria. Unfortunately, the versatility of the acridine molecule is not entirely explored still. If new approaches may overcome the drawbacks of the acridines such as resistance of pathogens and tumour cells in synthesis and formulation acridine analogues will become a useful drug candidate for the treatment of diseases mentioned above. So this article aims to seek the attention of researchers in the acridine to utilise it’s a wide range of biological activities in the development of novel drug molecules for the various diseases in the future.

Alzheimer’s Disease Targeted Nano-Based Drug Delivery Systems

2020 ◽  
Vol 21 (7) ◽  
pp. 628-646
Author(s):  
Gülcem Altinoglu ◽  
Terin Adali
Keyword(s):  
Alzheimer’S Disease ◽  
Drug Delivery ◽  
Alzheimer's Disease ◽  
Neurological Diseases ◽  
Sustained Drug Release ◽  
Physiochemical Properties ◽  
Conventional Drug ◽  
Health Care Burden ◽  
The Central Nervous System ◽  
Effective Drugs

Alzheimer’s disease (AD) is the most common neurodegenerative disease, and is part of a massive and growing health care burden that is destroying the cognitive function of more than 50 million individuals worldwide. Today, therapeutic options are limited to approaches with mild symptomatic benefits. The failure in developing effective drugs is attributed to, but not limited to the highly heterogeneous nature of AD with multiple underlying hypotheses and multifactorial pathology. In addition, targeted drug delivery to the central nervous system (CNS), for the diagnosis and therapy of neurological diseases like AD, is restricted by the challenges posed by blood-brain interfaces surrounding the CNS, limiting the bioavailability of therapeutics. Research done over the last decade has focused on developing new strategies to overcome these limitations and successfully deliver drugs to the CNS. Nanoparticles, that are capable of encapsulating drugs with sustained drug release profiles and adjustable physiochemical properties, can cross the protective barriers surrounding the CNS. Thus, nanotechnology offers new hope for AD treatment as a strong alternative to conventional drug delivery mechanisms. In this review, the potential application of nanoparticle based approaches in Alzheimer’s disease and their implications in therapy is discussed.

Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

2020 ◽  
Vol 13 (4) ◽  
pp. 273-294 ◽  
Author(s):  
Elahe Zarini-Gakiye ◽  
Javad Amini ◽  
Nima Sanadgol ◽  
Gholamhassan Vaezi ◽  
Kazem Parivar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Trials ◽  
Small Molecules ◽  
Clinical Trial Design ◽  
Treatment Approaches ◽  
Drug Candidates ◽  
Novel Treatments ◽  
Approved Drugs ◽  
Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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

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.

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

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.

scholarly journals Exploitation of Marine Molecules to Manage Alzheimer’s Disease

Marine Drugs ◽  
2021 ◽  
Vol 19 (7) ◽  
pp. 373
Author(s):  
Marisa Silva ◽  
Paula Seijas ◽  
Paz Otero
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Nmda Receptor Antagonists ◽  
Average Life ◽  
Average Life Expectancy ◽  
Large Reservoir ◽  
Drug Candidates ◽  
Neurodegenerative Process ◽  
Main Action

Neurodegenerative diseases are sociosanitary challenges of today, as a result of increased average life expectancy, with Alzheimer’s disease being one of the most prevalent. This pathology is characterized by brain impairment linked to a neurodegenerative process culminating in cognitive decline and behavioral disorders. Though the etiology of this pathology is still unknown, it is usually associated with the appearance of senile plaques and neurofibrillary tangles. The most used prophylaxis relies on anticholinesterase drugs and NMDA receptor antagonists, whose main action is to relieve symptoms and not to treat or prevent the disease. Currently, the scientific community is gathering efforts to disclose new natural compounds effective against Alzheimer’s disease and other neurodegenerative pathologies. Marine natural products have been shown to be promising candidates, and some have been proven to exert a high neuroprotection effect, constituting a large reservoir of potential drugs and nutraceutical agents. The present article attempts to describe the processes of extraction and isolation of bioactive compounds derived from sponges, algae, marine bacteria, invertebrates, crustaceans, and tunicates as drug candidates against AD, with a focus on the success of pharmacological activity in the process of finding new and effective drug compounds.

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