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Rational Design of Dual Inhibitors for Alzheimer's Disease: Insights from Computational Screening of BACE1 and GSK-3β.

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العنوان: Rational Design of Dual Inhibitors for Alzheimer's Disease: Insights from Computational Screening of BACE1 and GSK-3β.
المؤلفون: Sai Varshini M; Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India., Reddy RA; Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India., Krishnamurthy PT; Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India., Selvaraj D; Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education and Research, Ooty, 643001, TN, India.
المصدر: Current computer-aided drug design [Curr Comput Aided Drug Des] 2024; Vol. 20 (6), pp. 998-1012.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Bentham Science Publishers Country of Publication: United Arab Emirates NLM ID: 101265750 Publication Model: Print Cited Medium: Internet ISSN: 1875-6697 (Electronic) Linking ISSN: 15734099 NLM ISO Abbreviation: Curr Comput Aided Drug Des Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Sharjah, U.A.E. ; San Francisco, CA : Bentham Science Publishers, c2005-
مواضيع طبية MeSH: Alzheimer Disease*/drug therapy , Amyloid Precursor Protein Secretases*/antagonists & inhibitors , Amyloid Precursor Protein Secretases*/metabolism , Aspartic Acid Endopeptidases*/antagonists & inhibitors , Aspartic Acid Endopeptidases*/metabolism , Glycogen Synthase Kinase 3 beta*/antagonists & inhibitors , Glycogen Synthase Kinase 3 beta*/metabolism , Molecular Docking Simulation* , Drug Design* , Molecular Dynamics Simulation*, Humans ; Enzyme Inhibitors/pharmacology ; Enzyme Inhibitors/chemistry
مستخلص: 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.
(Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
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فهرسة مساهمة: Keywords: AD; BACE1; GSK-3β; MMGBSA; molecular docking; molecular dynamic simulation.
المشرفين على المادة: EC 3.4.- (Amyloid Precursor Protein Secretases)
EC 3.4.23.- (Aspartic Acid Endopeptidases)
EC 2.7.11.1 (Glycogen Synthase Kinase 3 beta)
EC 3.4.23.46 (BACE1 protein, human)
0 (Enzyme Inhibitors)
تواريخ الأحداث: Date Created: 20231103 Date Completed: 20240715 Latest Revision: 20240715
رمز التحديث: 20240715
DOI: 10.2174/0115734099270256231018072007
PMID: 37921183
قاعدة البيانات: MEDLINE
الوصف
تدمد:1875-6697
DOI:10.2174/0115734099270256231018072007