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 Molecular Hybridization as a Tool in the Design of Multi-target Directed Drug Candidates for Neurodegenerative Diseases

2020 ◽  
Vol 18 (5) ◽  
pp. 348-407 ◽  
Author(s):  
Vanessa Silva Gontijo ◽  
Flávia P. Dias Viegas ◽  
Cindy Juliet Cristancho Ortiz ◽  
Matheus de Freitas Silva ◽  
Caio Miranda Damasio ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Rational Design ◽  
Brain Regions ◽  
Molecular Hybridization ◽  
Drug Candidate ◽  
New Paradigm ◽  
New Approach ◽  
Biological Targets ◽  
Drug Candidates ◽  
Biochemical Pathways

Neurodegenerative Diseases (NDs) are progressive multifactorial neurological pathologies related to neuronal impairment and functional loss from different brain regions. Currently, no effective treatments are available for any NDs, and this lack of efficacy has been attributed to the multitude of interconnected factors involved in their pathophysiology. In the last two decades, a new approach for the rational design of new drug candidates, also called multitarget-directed ligands (MTDLs) strategy, has emerged and has been used in the design and for the development of a variety of hybrid compounds capable to act simultaneously in diverse biological targets. Based on the polypharmacology concept, this new paradigm has been thought as a more secure and effective way for modulating concomitantly two or more biochemical pathways responsible for the onset and progress of NDs, trying to overcome low therapeutical effectiveness. As a complement to our previous review article (Curr. Med. Chem. 2007, 14 (17), 1829-1852. https://doi.org/10.2174/092986707781058805), herein we aimed to cover the period from 2008 to 2019 and highlight the most recent advances of the exploitation of Molecular Hybridization (MH) as a tool in the rational design of innovative multifunctional drug candidate prototypes for the treatment of NDs, specially focused on AD, PD, HD and ALS.

scholarly journals Pleiotropic Protective Effects of Phytochemicals in Alzheimer's Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-11 ◽  
Author(s):  
Sergio Davinelli ◽  
Nadia Sapere ◽  
Davide Zella ◽  
Renata Bracale ◽  
Mariano Intrieri ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Protective Effects ◽  
Drug Candidates ◽  
Molecular Events ◽  
Therapeutic Value ◽  
Phytochemical Compounds ◽  
Multiple Levels ◽  
The Brain

Alzheimer’s disease (AD) is a severe chronic neurodegenerative disorder of the brain characterised by progressive impairment in memory and cognition. In the past years an intense research has aimed at dissecting the molecular events of AD. However, there is not an exhaustive knowledge about AD pathogenesis and a limited number of therapeutic options are available to treat this neurodegenerative disease. Consequently, considering the heterogeneity of AD, therapeutic agents acting on multiple levels of the pathology are needed. Recent findings suggest that phytochemicals compounds with neuroprotective features may be an important resources in the discovery of drug candidates against AD. In this paper we will describe some polyphenols and we will discuss their potential role as neuroprotective agents. Specifically, curcumin, catechins, and resveratrol beyond their antioxidant activity are also involved in antiamyloidogenic and anti-inflammatory mechanisms. We will focus on specific molecular targets of these selected phytochemical compounds highlighting the correlations between their neuroprotective functions and their potential therapeutic value in AD.

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.

scholarly journals The Impact of Systemic Inflammation on Alzheimer’s Disease Pathology

2022 ◽  
Vol 12 ◽  
Author(s):  
Junhua Xie ◽  
Lien Van Hoecke ◽  
Roosmarijn E. Vandenbroucke
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Neurodegenerative Disorder ◽  
Peripheral Inflammation ◽  
Comprehensive Overview ◽  
Age Related ◽  
Symptomatic Medication ◽  
Inflammatory Processes ◽  
The Impact

Alzheimer’s disease (AD) is a devastating age-related neurodegenerative disorder with an alarming increasing prevalence. Except for the recently FDA-approved Aducanumab of which the therapeutic effect is not yet conclusively proven, only symptomatic medication that is effective for some AD patients is available. In order to be able to design more rational and effective treatments, our understanding of the mechanisms behind the pathogenesis and progression of AD urgently needs to be improved. Over the last years, it became increasingly clear that peripheral inflammation is one of the detrimental factors that can contribute to the disease. Here, we discuss the current understanding of how systemic and intestinal (referred to as the gut-brain axis) inflammatory processes may affect brain pathology, with a specific focus on AD. Moreover, we give a comprehensive overview of the different preclinical as well as clinical studies that link peripheral Inflammation to AD initiation and progression. Altogether, this review broadens our understanding of the mechanisms behind AD pathology and may help in the rational design of further research aiming to identify novel therapeutic targets.

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.

Exploring the Anti-Neuroinflammatory Potential of Steroid and Terpenoid-Derived Phytochemicals to Combat Alzheimer's Disease

2021 ◽  
Vol 26 ◽  
Author(s):  
Md. Tanvir Kabir ◽  
Md. Sahab Uddin ◽  
Sonia Zaman ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Symptomatic Treatment ◽  
Drug Candidates ◽  
Age Related ◽  
Inflammatory Processes ◽  
Pharmacologically Active ◽  
And Behavior ◽  
Therapeutic Activities

: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder that significantly affects cognitive functions in a way that causes loss of memory, thinking, and behavior. Multiple studies revealed that neuroinflammation associated with AD is linked with the amyloid-beta deposition in the brain. Elevated levels of expression of cytokines, microglial activation, nuclear factor kappa B, and reactive oxygen species play roles in ADrelated inflammatory processes. Indeed, effective therapeutic approaches are urgently required to develop therapeutic agents to prevent and treat AD. So far, many anti-AD drug candidates have failed in the clinical stages and currently available drugs only provide symptomatic treatment. In recent times, pharmacologically active phytochemicals have been found to possess promising anti-neuroinflammatory effects; therefore these natural products can be useful in the AD treatment. In this review, we have comprehensively discussed the role of neuroinflammation and the molecular processes altered by multiple steroid and terpenoid-derived phytochemicals in various AD-related neuroinflammatory pathways. Indeed, steroid and terpenoid-derived phytochemicals show important therapeutic activities, which can be useful in ameliorating and treating AD-related neurodegeneration.

Design of Multi-target Directed Ligands as a Modern Approach for the Development of Innovative Drug Candidates for Alzheimer’s Disease

2018 ◽  
pp. 255-351 ◽  
Author(s):  
Cindy Juliet Cristancho Ortiz ◽  
Matheus de Freitas Silva ◽  
Vanessa Silva Gontijo ◽  
Flávia Pereira Dias Viegas ◽  
Kris Simone Tranches Dias ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Innovative Drug ◽  
Modern Approach ◽  
Drug Candidates

scholarly journals Hybrid Quinoline-Thiosemicarbazone Therapeutics as a New Treatment Opportunity for Alzheimer’s Disease‒Synthesis, In Vitro Cholinesterase Inhibitory Potential and Computational Modeling Analysis

Molecules ◽  
2021 ◽  
Vol 26 (21) ◽  
pp. 6573
Author(s):  
Sumera Zaib ◽  
Rubina Munir ◽  
Muhammad Tayyab Younas ◽  
Naghmana Kausar ◽  
Aliya Ibrar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Symptomatic Relief ◽  
Synthetic Approach ◽  
Spectroscopic Techniques ◽  
Disease Heterogeneity ◽  
Standard Drug ◽  
Drug Candidates

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia worldwide. The limited pharmacological approaches based on cholinesterase inhibitors only provide symptomatic relief to AD patients. Moreover, the adverse side effects such as nausea, vomiting, loss of appetite, muscle cramps, and headaches associated with these drugs and numerous clinical trial failures present substantial limitations on the use of medications and call for a detailed insight of disease heterogeneity and development of preventive and multifactorial therapeutic strategies on urgent basis. In this context, we herein report a series of quinoline-thiosemicarbazone hybrid therapeutics as selective and potent inhibitors of cholinesterases. A facile multistep synthetic approach was utilized to generate target structures bearing multiple sites for chemical modifications and establishing drug-receptor interactions. The structures of all the synthesized compounds were fully established using readily available spectroscopic techniques (FTIR, 1H- and 13C-NMR). In vitro inhibitory results revealed compound 5b as a promising and lead inhibitor with an IC50 value of 0.12 ± 0.02 μM, a 5-fold higher potency than standard drug (galantamine; IC50 = 0.62 ± 0.01 μM). The synergistic effect of electron-rich (methoxy) group and ethylmorpholine moiety in quinoline-thiosemicarbazone conjugates contributes significantly in improving the inhibition level. Molecular docking analysis revealed various vital interactions of potent compounds with amino acid residues and reinforced the in vitro results. Kinetics experiments revealed the competitive mode of inhibition while ADME properties favored the translation of identified inhibitors into safe and promising drug candidates for pre-clinical testing. Collectively, inhibitory activity data and results from key physicochemical properties merit further research to ensure the design and development of safe and high-quality drug candidates for Alzheimer’s disease.

scholarly journals Study of the Alkaloid Polyneuridine as a Drug Candidate for Therapy of Alzheimer's Disease

2021 ◽  
Vol 11 (4) ◽  
pp. 4508-4518
Author(s):  
Viviane Lima Silva ◽  
Valéria Lima Silva
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Plant Species ◽  
Neurodegenerative Disorder ◽  
Indole Alkaloid ◽  
Drug Candidate ◽  
Irreversible Loss ◽  
Anticholinesterase Property ◽  
Cholinergic Hypofunction ◽  
Anticholinesterase Properties

Alzheimer's disease is characterized by the progressive and irreversible loss of natural cognitive functions in most elderly people. There is currently no cure for this neurodegenerative disorder, but there are therapies available on the market based on substances that inhibit acetylcholinesterase and cognitive symptoms as a way to improve cholinergic hypofunction. Polyneuridine is the main indole alkaloid extracted from the bark and leaves of Aspidosperma polyneuron, a brazilian plant species popularly known as peroba-rosa. The objective of this work is to investigate, through a scientific prospection, the polyneuridine alkaloid, as well as its anticholinesterase property, since it is known that the therapy of this disease is based on cholinesterase inhibitors. To carry out the study, two of the main publication databases of journals such as PubMed and Web of Science were analyzed. To search for scientific production, we inserted the following keywords combined with the terms in english to carry out the search in international databases: “Polyneuridine”, “Polyneuridine AND anticholinesterase properties”, “Polyneuridine AND Alzheimer's disease”. The need for studies on this alkaloid is urgent, especially since Brazil holds the plant species that produces the most polyneuridine, but the plant species Aspidosperma polyneuron is on the red line of extinction due to the unbridled exploitation of its wood. It is concluded that if this exploration scenario continues, Brazil will lose a very important pharmacological genetic resource of its plant flora.

scholarly journals Hypoxia-Induced Neuroinflammation in Alzheimer’s Disease: Potential Neuroprotective Effects of Centella asiatica

2021 ◽  
Vol 12 ◽  
Author(s):  
Aqilah Hambali ◽  
Jaya Kumar ◽  
Nur Fariesha Md Hashim ◽  
Sandra Maniam ◽  
Muhammad Zulfadli Mehat ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Therapeutic Agent ◽  
Neurodegenerative Disorder ◽  
Centella Asiatica ◽  
Neuroprotective Effects ◽  
Drug Candidates ◽  
The Brain ◽  
Pro Inflammatory Cytokines

Alzheimer’s disease (AD) is a neurodegenerative disorder that is characterised by the presence of extracellular beta-amyloid fibrillary plaques and intraneuronal neurofibrillary tau tangles in the brain. Recurring failures of drug candidates targeting these pathways have prompted research in AD multifactorial pathogenesis, including the role of neuroinflammation. Triggered by various factors, such as hypoxia, neuroinflammation is strongly linked to AD susceptibility and/or progression to dementia. Chronic hypoxia induces neuroinflammation by activating microglia, the resident immune cells in the brain, along with an increased in reactive oxygen species and pro-inflammatory cytokines, features that are common to many degenerative central nervous system (CNS) disorders. Hence, interests are emerging on therapeutic agents and plant derivatives for AD that target the hypoxia-neuroinflammation pathway. Centella asiatica is one of the natural products reported to show neuroprotective effects in various models of CNS diseases. Here, we review the complex hypoxia-induced neuroinflammation in the pathogenesis of AD and the potential application of Centella asiatica as a therapeutic agent in AD or dementia.

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