Imidazo[2,1-b][1,3]thiazine Derivatives as Potential Modulators of Alpha-Synuclein Amyloid Aggregation DOI
Indrė Misiūnaitė, Kamilė Mikalauskaitė,

Martyna Paulauskaitė

et al.

ACS Chemical Neuroscience, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 27, 2024

Insoluble amyloid fibrils accumulate in the intercellular spaces of organs and tissues, leading to various amyloidosis-related disorders human body. Specifically, Parkinson's disease is associated with aggregation alpha-synuclein. However, current treatments for primarily focus on managing motor symptoms slowing progression. Efforts prevent halt progression these diseases involve search small molecular compounds. In this work, we synthesized imidazo[2,1-b][1,3]thiazines an atom-economic way by cyclization 2-alkynylthioimidazoles using 10% AuCl as catalyst. We identified several compounds specific functional groups capable both inhibiting alpha-synuclein redirecting fibril formation pathway. The investigation into how substances function revealed that imidazo[2,1-b][1,3]thiazine derivatives can influence ways. They not only inhibit primary nucleation process maintain a balance toward nonaggregated protein states but also stabilize smaller oligomeric species cause unique structures forms. These could potentially be used developing highly efficient, weight inhibitors.

Language: Английский

Screening Techniques for Drug Discovery in Alzheimer’s Disease DOI Creative Commons
Sandra Maniam, Subashani Maniam

ACS Omega, Journal Year: 2024, Volume and Issue: 9(6), P. 6059 - 6073

Published: Feb. 5, 2024

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible impairment of memory other cognitive functions the aging brain. Pathways such as amyloid beta neurotoxicity, tau pathogenesis neuroinflammatory have been used to understand AD, despite not knowing definite molecular mechanism which causes this disease. This review attempts summarize small molecules that target these pathways using various techniques involving high-throughput screening, modeling, custom bioassays, spectroscopic detection tools. Novel evolving screening methods developed advance drug discovery initiatives in AD research are also highlighted.

Language: Английский

Citations

12
Inhibition and Degradation of Amyloid Beta Fibrils by Peptide Inhibitors DOI
Abdul Majid, Sanjeev Garg

The Journal of Physical Chemistry B, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 2, 2025

Abnormal amyloid beta (Aβ) aggregation in the form of plaques and its deposition across human nerve cells are a major hallmark Alzheimer's disease. Aβ dynamics and, more importantly, various drugs' effects, either to inhibit fibril or degrade mature fibrils, have been an area active research. Large molecule (peptide-based) inhibitors, such as decapeptide (RYYAAFFARR) pentapeptide (LPFFD), show inhibition/degradation effects on fibrils. Herein, mathematical model has proposed. The simulates inhibitory/degradative action peptide inhibitors fibrillation. Model parameters tuned by curve fitting experimental data. is used predict data at different initial dose/fibril concentrations. predicted results observed be good agreement with reported data, demonstrating model's applicability molecular level. Sensitivity analyses concentration further establish robustness proposed model.

Language: Английский

Citations

1
Design, synthesis and bioevaluation of 1,2,4-thiadiazolidine-3,5-dione derivatives as potential GSK-3β inhibitors for the treatment of Alzheimer's disease DOI

Yongxi Dong,

Jun Lü, Shanhui Zhang

et al.

Bioorganic Chemistry, Journal Year: 2023, Volume and Issue: 134, P. 106446 - 106446

Published: Feb. 25, 2023

Language: Английский

Citations

17
Recent advancements in the therapeutic approaches for Alzheimer's disease treatment: Current and future perspective DOI Creative Commons
Amit Sharma, Santosh Rudrawar, Sandip B. Bharate

et al.

RSC Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 6, 2024

This review collates the recent information related to proposed hypotheses for AD etiology and advances in various therapeutic options, with a particular emphasis on clinical candidates.

Language: Английский

Citations

4
Intranasal amyloid model of Alzheimer’s disease - potential opportunities and challenges DOI
Rakesh Kumar Singh

Pharmacological Reports, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 8, 2025

Language: Английский

Citations

0
Role of Quinoline and Indole-Based Heterocycles in revolutionizing Alzheimer’s drug discovery – Promising futuristic structural designs DOI
Atukuri Dorababu

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 103606 - 103606

Published: May 1, 2025

Language: Английский

Citations

0
Modeling Inhibitory Effects of Chlorogenic Acid on Amyloid Beta Aggregation DOI
Abdul Majid, Sanjeev Garg

Industrial & Engineering Chemistry Research, Journal Year: 2024, Volume and Issue: 63(17), P. 7636 - 7645

Published: April 17, 2024

Amyloid β (Aβ) aggregation is considered one of the major factors in Alzheimer's disease (AD) pathogenesis. Seeking therapeutic molecules that could inhibit effectively has been a research focus recent years. Chlorogenic acid (CGA) reported to have an inhibition effect on Aβ aggregation, and its effectiveness be enhanced when loaded with selenium nanoparticles. Herein, previously kinetic model based radical polymerization studying only modified. The modified used study inhibitory effects CGA nanoparticles aggregation. Parameter tuning done experimental data estimate values new parameters introduced model. simulated results from are good agreement at different doses both Moreover, sensitivity analyses demonstrate robustness It hypothesized may help elucidate Aβ-drug interactions revealing insights also other drugs, such as polyphenols, metal chelators, peptides, show similar trend for fibrillation.

Language: Английский

Citations

3
Development of scoring-assisted generative exploration (SAGE) and its application to dual inhibitor design for acetylcholinesterase and monoamine oxidase B DOI Creative Commons
Hocheol Lim

Journal of Cheminformatics, Journal Year: 2024, Volume and Issue: 16(1)

Published: May 24, 2024

Abstract De novo molecular design is the process of searching chemical space for drug-like molecules with desired properties, and deep learning has been recognized as a promising solution. In this study, I developed an effective computational method called Scoring-Assisted Generative Exploration (SAGE) to enhance diversity property optimization through virtual synthesis simulation, generation bridged bicyclic rings, multiple scoring models drug-likeness. six protein targets, SAGE generated high scores within reasonable numbers steps by optimizing target specificity without constraint even constraints such synthetic accessibility, solubility, metabolic stability. Furthermore, suggested top-ranked molecule dual inhibitors acetylcholinesterase monoamine oxidase B optimization. Therefore, can generate properties simultaneously, indicating importance de strategies in future drug discovery development. Scientific contribution The scientific study lies development method, novel approach that significantly enhances design. uniquely integrates complex optimize comprehensively. By efficiently generating meet broad spectrum pharmacological criteria—including specificity, stability—within number steps, represents substantial advancement over traditional methods. Additionally, application discover not only demonstrates its potential streamline but also highlights capacity create more precisely targeted therapies. This emphasizes critical evolving role reshaping development, providing avenues innovative therapeutic discoveries.

Language: Английский

Citations

3
Alzheimer’s Disease: A Suitable Case for Treatment with Precision Medicine? DOI Creative Commons

Ernest K. J. Pauwels,

Gerard J. Boer

Medical Principles and Practice, Journal Year: 2024, Volume and Issue: 33(4), P. 301 - 309

Published: Jan. 1, 2024

Alzheimer’s disease (AD) is the most common cause of neurodegenerative impairment in elderly people. Clinical characteristics include short-term memory loss, confusion, hallucination, agitation, and behavioral disturbance. Owing to evolving research biomarkers, AD can be discovered at early onset, but currently considered a continuum, which suggests that pharmacotherapy efficacious preclinical phase, possibly 15–20 years before discernible onset. Present developments therapy aim respond this understanding go beyond drug families relieve clinical symptoms. Another important factor development emergence precision medicine aims tailor treatment specific patients or patient subgroups. This relatively new platform would categorize on basis parameters like aspects, brain imaging, genetic profiling, genetics, epidemiological factors. review enlarges recent progress design use antisense molecules, antibodies, antioxidants, small gene editing stop reverse relevant biomarkers.

Language: Английский

Citations

2
Protein aggregation and neurodegenerative disease: Structural outlook for the novel therapeutics DOI Creative Commons
Sharif Arar, Md. Anzarul Haque, Rakez Kayed

et al.

Proteins Structure Function and Bioinformatics, Journal Year: 2023, Volume and Issue: unknown

Published: Aug. 2, 2023

Abstract Before the controversial approval of humanized monoclonal antibody lecanemab, which binds to soluble amyloid‐β protofibrils, all treatments available earlier, for Alzheimer's disease (AD) were symptomatic. The researchers are still struggling find a breakthrough in AD therapeutic medicine, is partially attributable lack understanding structural information associated with intrinsically disordered proteins and amyloids. One major challenges this area research understand diversity under vitro conditions. Therefore, review, we have summarized applications biophysical methods, aimed shed some light on heterogeneity, pathogenicity, structures mechanisms protein aggregates proteinopathies including AD. This review will also rationalize strategies modulating disease‐relevant pathogenic entities by small molecules using biology approaches characterization. We highlighted tools techniques simulate vivo conditions native cytotoxic tau/amyloids assemblies, urge new chemical replicate assemblies similar those conditions, addition designing novel potential drugs.

Language: Английский

Citations

5