Affiliation:
1. Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty,
643001, TN, India
2. Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and
Research, Ooty, 643001, TN, India
Abstract
Background:
Alzheimer's disease (AD) is one of the most concerned neurodegenerative
disorders across the world characterized by amyloid-beta (Aβ) plaques and neurofibrillary
tangles (NFTs), leading to cognitive decline and memory loss. Targeting key pathways involved
in AD like Aβ and NFT pathways, are crucial for the development of effective therapeutic strategies.
In this study, we aimed to identify and establish promising dual inhibitors targeting
BACE1 and GSK-3β, two proteins implicated in Aβ and NFT formation respectively.
Methods:
We have used molecular docking, ADME property analysis, and MMGBSA calculations
for the identification of hit molecules and further evaluation of binding affinity, drug-like
properties, and stability against BACE1 and GSK-3β.
Results:
Our results demonstrated strong binding affinities of ZINC000034853956 towards the
active sites of both proteins, with favorable interactions involving key residues crucial for inhibitory
activity. Additionally, ZINC000034853956 exhibited favorable drug-like properties. MD
simulations revealed the stable binding of ZINC000034853956 to both BACE1 and GSK-3β
over a 50 ns period, with consistent ligand-protein interactions, such as hydrogen bonding and
hydrophobic contacts. These findings highlight the potential of ZINC000034853956 as a promising
candidate for AD treatment, acting as a dual inhibitor targeting both BACE1 and GSK-3β.
Overall, our study provides valuable insights into the potential of ZINC000034853956 as a dual
inhibitor for AD. The strong binding affinity, favorable drug-like properties, and stability observed
in MD simulations support its suitability for further optimization and preclinical studies.
Conclusion:
Further investigations are warranted to elucidate the precise molecular mechanisms
and therapeutic benefits of ZINC000034853956. Our findings offer hope for the development of
novel therapeutic interventions targeting crucial pathways involved in AD neurodegeneration.
Publisher
Bentham Science Publishers Ltd.
Subject
Drug Discovery,Molecular Medicine,General Medicine
Cited by
1 articles.
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