An In Silico Study Based on QSAR and Molecular Docking and Molecular Dynamics Simulation for the Discovery of Novel Potent Inhibitor against AChE DOI Creative Commons

Meriem Khedraoui,

Oussama Abchır, Hassan Nour

et al.

Pharmaceuticals, Journal Year: 2024, Volume and Issue: 17(7), P. 830 - 830

Published: June 25, 2024

Acetylcholinesterase (AChE) is one of the main drug targets for treating Alzheimer’s disease. This current study relies on multiple molecular modeling approaches to develop new potent inhibitors AChE. We explored a 2D QSAR using statistical method linear regression based set substituted 5-phenyl-1,3,4-oxadiazole and N-benzylpiperidine analogs, which were recently synthesized proved their inhibitory activities against acetylcholinesterase (AChE). The descriptors, polar surface area, dipole moment, weight are key structural properties governing AChE inhibition activity. MLR model was selected its parameters: R2 = 0.701, R2test 0.76, Q2CV 0.638, RMSE 0.336, demonstrating predictive reliability. Randomization tests, VIF applicability domain tests adopted verify model’s robustness. As result, 11 molecules designed with higher anti-Alzheimer’s than molecule. demonstrated improved pharmacokinetic through an in silico ADMET study. A docking conducted explore mechanisms binding affinities active site. scores compounds M1, M2, M6 (−12.6 kcal/mol), (−13 (−12.4 respectively, standard inhibitor Donepezil score (−10.8 kcal/mol). Molecular dynamics simulations over 100 ns used validate results, indicating that M1 M2 remain stable site, confirming potential as promising anti-AChE inhibitors.

Language: Английский

Neurotransmitters—Key Factors in Neurological and Neurodegenerative Disorders of the Central Nervous System DOI Open Access
Raluca Ioana Teleanu, Adelina-Gabriela Niculescu, Eugenia Roza

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 5954 - 5954

Published: May 25, 2022

Neurotransmitters are molecules that amplify, transmit, and convert signals in cells, having an essential role information transmission throughout the nervous system. Hundreds of such chemicals have been discovered last century, continuing to be identified studied concerning their action on brain health. These substances observed influence numerous functions, including emotions, thoughts, memories, learning, movements. Thus, disturbances neurotransmitters' homeostasis started being correlated with a plethora neurological neurodegenerative disorders. In this respect, present paper aims describe most important neurotransmitters, broadly classified into canonical (e.g., amino acids, monoamines, acetylcholine, purines, soluble gases, neuropeptides) noncanonical neurotransmitters exosomes, steroids, D-aspartic acid), explain link some relevant conditions. Moreover, brief overview recently developed detection methods is offered, followed by several considerations modulation these towards restoring homeostasis.

Language: Английский

Citations

257
Recent advances in Alzheimer’s disease: Mechanisms, clinical trials and new drug development strategies DOI Creative Commons
Jifa Zhang, Yinglu Zhang, Jiaxing Wang

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Aug. 23, 2024

Abstract Alzheimer’s disease (AD) stands as the predominant form of dementia, presenting significant and escalating global challenges. Its etiology is intricate diverse, stemming from a combination factors such aging, genetics, environment. Our current understanding AD pathologies involves various hypotheses, cholinergic, amyloid, tau protein, inflammatory, oxidative stress, metal ion, glutamate excitotoxicity, microbiota-gut-brain axis, abnormal autophagy. Nonetheless, unraveling interplay among these pathological aspects pinpointing primary initiators require further elucidation validation. In past decades, most clinical drugs have been discontinued due to limited effectiveness or adverse effects. Presently, available primarily offer symptomatic relief often accompanied by undesirable side However, recent approvals aducanumab ( 1 ) lecanemab 2 Food Drug Administration (FDA) present potential in disrease-modifying Nevertheless, long-term efficacy safety need Consequently, quest for safer more effective persists formidable pressing task. This review discusses pathogenesis, advances diagnostic biomarkers, latest updates trials, emerging technologies drug development. We highlight progress discovery selective inhibitors, dual-target allosteric modulators, covalent proteolysis-targeting chimeras (PROTACs), protein-protein interaction (PPI) modulators. goal provide insights into prospective development application novel drugs.

Language: Английский

Citations

129
Alzheimer's Disease Puzzle: Delving into Pathogenesis Hypotheses DOI Creative Commons
Mohammad Nasb,

Weichu Tao,

Ning Chen

et al.

Aging and Disease, Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 8, 2023

Alzheimer's disease (AD) is a prevalent neurodegenerative characterized by both amnestic and non-amnestic clinical manifestations. It accounts for approximately 60-70% of all dementia cases worldwide. With the increasing number AD patients, elucidating underlying mechanisms developing corresponding interventional strategies are necessary. Hypotheses about such as amyloid cascade, Tau hyper-phosphorylation, neuroinflammation, oxidative stress, mitochondrial dysfunction, cholinergic, vascular hypotheses not mutually exclusive, them play certain role in development AD. The cascade hypothesis currently most widely studied; however, other also gaining support. This article summarizes recent evidence regarding major pathological their potential interplay, well strengths weaknesses each implications effective treatments. could stimulate further studies promote more therapeutic

Language: Английский

Citations

65
6,7-Coumarin-heterocyclic hybrids: A comprehensive review of their natural sources, synthetic approaches, and bioactivity DOI
Nameer Mazin Zeki, Yasser Fakri Mustafa

Journal of Molecular Structure, Journal Year: 2024, Volume and Issue: 1303, P. 137601 - 137601

Published: Jan. 22, 2024

Language: Английский

Citations

21
Alzheimer’s disease and its treatment–yesterday, today, and tomorrow DOI Creative Commons

A. Y. Kim,

Salman Al Jerdi, Ryan B. MacDonald

et al.

Frontiers in Pharmacology, Journal Year: 2024, Volume and Issue: 15

Published: May 24, 2024

Alois Alzheimer described the first patient with Alzheimer’s disease (AD) in 1907 and today AD is most frequently diagnosed of dementias. a multi-factorial neurodegenerative disorder familial, life style comorbidity influences impacting global population more than 47 million projected escalation by 2050 to exceed 130 million. In USA demographic encompasses approximately six individuals, expected increase surpass 13 2050, antecedent phase AD, recognized as mild cognitive impairment (MCI), involves nearly 12 individuals. The economic outlay for management AD-related decline estimated at 355 billion USD. addition, intensifying prevalence cases countries modest intermediate income further enhances urgency therapeutically cost-effective treatments improving quality patients their families. This narrative review evaluates pathophysiological basis an initial focus on therapeutic efficacy limitations existing drugs that provide symptomatic relief: acetylcholinesterase inhibitors (AChEI) donepezil, galantamine, rivastigmine, N-methyl-D-aspartate receptor (NMDA) allosteric modulator, memantine. hypothesis amyloid-β (Aβ) tau are appropriate targets have potential halt progress critically analyzed particular clinical trial data anti-Aβ monoclonal antibodies (MABs), namely, aducanumab, lecanemab donanemab. challenges dogma targeting Aβ will benefit majority subjects MABs unlikely be “magic bullet”. A comparison benefits disadvantages different classes forms determining new directions research alternative drug undergoing pre-clinical assessments. we discuss stress importance treatment co-morbidities, including hypertension, diabetes, obesity depression known risk developing AD.

Language: Английский

Citations

18
The duality of amyloid-β: its role in normal and Alzheimer’s disease states DOI Creative Commons
Ali Azargoonjahromi

Molecular Brain, Journal Year: 2024, Volume and Issue: 17(1)

Published: July 17, 2024

Abstract Alzheimer’s disease (AD) is a degenerative neurological condition that gradually impairs cognitive abilities, disrupts memory retention, and impedes daily functioning by impacting the cells of brain. A key characteristic AD accumulation amyloid-beta (Aβ) plaques, which play pivotal roles in progression. These plaques initiate cascade events including neuroinflammation, synaptic dysfunction, tau pathology, oxidative stress, impaired protein clearance, mitochondrial disrupted calcium homeostasis. Aβ also closely associated with other hallmark features AD, underscoring its significance. generated through cleavage amyloid precursor (APP) plays dual role depending on processing pathway. The non-amyloidogenic pathway reduces production has neuroprotective anti-inflammatory effects, whereas amyloidogenic leads to peptides, Aβ40 Aβ42, contribute neurodegeneration toxic effects AD. Understanding multifaceted Aβ, particularly crucial for developing effective therapeutic strategies target metabolism, aggregation, clearance aim mitigating detrimental consequences disease. This review aims explore mechanisms functions under normal abnormal conditions, examining both beneficial effects.

Language: Английский

Citations

18
Cellular and organismal function of choline metabolism DOI
Timothy C. Kenny, Samantha G. Scharenberg, Monther Abu-Remaileh

et al.

Nature Metabolism, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

Citations

2
Current Advances in the Therapeutic Potential of Scutellarin: Novel Applications, Mechanisms, and Future Challenges. DOI Creative Commons
Great Iruoghene Edo, Alice Njolke Mafe, Patrick Othuke Akpoghelie

et al.

Phytomedicine Plus, Journal Year: 2025, Volume and Issue: unknown, P. 100754 - 100754

Published: Jan. 1, 2025

Language: Английский

Citations

2
Understanding of Alzheimer's Disease Pathophysiology for Therapeutic Implications of Natural Products as Neuroprotective Agents DOI

Sneh Prabha,

Arunabh Choudhury,

Asimul Islam

et al.

Ageing Research Reviews, Journal Year: 2025, Volume and Issue: unknown, P. 102680 - 102680

Published: Feb. 1, 2025

Language: Английский

Citations

2
Muscarinic acetylcholine receptors for psychotic disorders: bench-side to clinic DOI Creative Commons
Samantha E. Yohn, Peter J. Weiden, Christian C. Felder

et al.

Trends in Pharmacological Sciences, Journal Year: 2022, Volume and Issue: 43(12), P. 1098 - 1112

Published: Oct. 20, 2022

Modern interest in muscarinic acetylcholine receptor (mAChR) activators for schizophrenia began the 1990s when xanomeline, an M1/M4-preferring mAChR agonist developed cognitive symptoms of Alzheimer's disease (AD), had unexpected antipsychotic activity. However, strategies to address tolerability concerns associated with activation peripheral mAChRs were not available at that time. The discovery specific targeted ligands and combination treatments reduce engagement have advanced potential as effective psychotic disorders. This review provides perspectives on background identification antipsychotics, advances preclinical understanding targets, current state under active clinical development schizophrenia.

Language: Английский

Citations

61