Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3ß for the Treatment of Alzheimer's Disease.
Curr Top Med Chem
; 24(19): 1738-1753, 2024.
Article
em En
| MEDLINE
| ID: mdl-38859777
ABSTRACT
BACKGROUND:
Alzheimer's disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3ß (GSK-3ß) and Acetylcholinesterase (AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it.OBJECTIVES:
To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3ß and AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3ß and AChE.METHODS:
In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger.RESULTS:
Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3ß and AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3ß and AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules.CONCLUSION:
Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3ß and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Acetilcolinesterase
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Inibidores da Colinesterase
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Doença de Alzheimer
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Simulação de Acoplamento Molecular
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Glicogênio Sintase Quinase 3 beta
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article