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Current Topics in Medicinal Chemistry


ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

Review Article

Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease

In Press, (this is not the final "Version of Record"). Available online 07 June, 2024
Author(s): Saurabh G. Londhe, Mangala Shenoy, Suvarna G. Kini, Vinayak Walhekar and Dileep Kumar*
Published on: 07 June, 2024

DOI: 10.2174/0115680266295740240602122613

Price: $95


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-3β (GSK-3β) 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-3β 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-3β 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-3β 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-3β 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-3β 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.

Keywords: Alzheimer’s disease, molecular docking, molecular dynamics, GSK-3β, AChE, Donepezil.

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